The Effect of Low-Dose Glucocorticoids Over Two Years on Weight and Blood Pressure in Rheumatoid Arthritis: Individual Patient Data From Five Randomized Trials.

BACKGROUND: Weight gain and hypertension are well known adverse effects of treatment with high-dose glucocorticoids. OBJECTIVE: To evaluate the effects of 2 years of low-dose glucocorticoid treatment in rheumatoid arthritis (RA). DESIGN: Pooled analysis of 5 randomized controlled trials with 2-year interventions allowing concomitant treatment with disease-modifying antirheumatic drugs. SETTING: 12 countries in Europe. PATIENTS: Early and established RA. INTERVENTION: Glucocorticoids at 7.5 mg or less prednisone equivalent per day. MEASUREMENTS: Coprimary end points were differences in change from baseline in body weight and mean arterial pressure after 2 years in intention-to-treat analyses. Difference in the change of number of antihypertensive drugs after 2 years was a secondary end point. Subgroup and sensitivity analyses were done to assess the robustness of primary findings. RESULTS: A total of 1112 participants were included (mean age, 61.4 years [SD, 14.5]; 68% women). Both groups gained weight in 2 years, but glucocorticoids led, on average, to 1.1 kg (95% CI, 0.4 to 1.8 kg; P < 0.001) more weight gain than the control treatment. Mean arterial pressure increased by about 2 mm Hg in both groups, with a between-group difference of -0.4 mm Hg (CI, -3.0 to 2.2 mm Hg; P = 0.187). These results were consistent in sensitivity and subgroup analyses. Most patients did not change the number of antihypertensive drugs, and there was no evidence of differences between groups. LIMITATION: Body composition was not assessed, and generalizability to non-European regions may be limited. CONCLUSION: This study provides robust evidence that low-dose glucocorticoids, received over 2 years for the treatment of RA, increase weight by about 1 kg but do not increase blood pressure. PRIMARY FUNDING SOURCE: None.

Long-term fracture risk in rheumatoid arthritis: impact of early sustained DAS28-remission and restored function, progressive erosive disease, body mass index, autoantibody positivity and glucocorticoids. A cohort study over 10 years.

BACKGROUND: Risk of fragility fractures in patients with rheumatoid arthritis (RA) is increased. Disease-related inflammation in RA is associated with low Bone Mineral Density (BMD). However, effects of specific disease factors on fracture occurrence and whether or not such disease effects are independent of BMD are unknown. METHODS: Analysis of fracture outcome in the prospective cohort of 2557 patients with early RA (67% women, mean age 58.1 ± 15.6 years) during an observation period of 10.6 ± 4.7 years. In 602 patients BMD was measured at baseline. The first major fragility fractures were considered. Kaplan-Meier and Cox regression analysis, adjusted for traditional factors, prior fracture, disease activity and period of inclusion, were used to estimate the risk of the outcome. RESULTS: During follow-up fracture occurred in 352 patients (13.8%), a rate of 13/1000 p-y. A proportional risk reduction for the outcome was associated with Body Mass Index (BMI) at baseline, BMI ≥ 30 kg/m2, and over the first two years sustained Disease Activity Score (DAS28)-remission, DAS28-low disease activity and Health Assessment Questionnaire (HAQ) ≤ 0.5. The proportional risk elevation for fractures was associated with BMI ≤ 20 kg/m2, DAS28 at baseline, 6-month and at 1-year, cumulative DAS28 over the two years, RF, erosion score progression at 2-year, HAQ score and HAQ ≥ 1 at 6-month and 1-year and showed a trend for ACPA positivity. The estimated fracture risk was increased in users of glucocorticoids (GC), associated with a higher GC-dosage at follow-ups and a higher cumulative dosage over two years, independently of disease activity. With adjustment for BMD, there was no difference in fracture outcome by exposure to GC. The effects of a higher BMI, DAS28-remission and low HAQ ≤ 0.5 attained at 6-month of treatment initiation and sustained up to 2 years, RF, ACPA, and erosion score progression at 2-year were independent of low BMD. CONCLUSIONS: This analysis supports importance of RA-specific risk factors in early RA for future major fragility fractures. Treat-to-target strategy and restored functional capacity in early RA-disease are important to prevent fractures. Autoantibody positivity, progressively erosive disease, and low weight could have additional value for personalized fracture preventive strategies in early RA.

Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis.

OBJECTIVE: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints. METHODS: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE). RESULTS: Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE. CONCLUSION: A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA.

Erosion-free rheumatoid arthritis: clinical and conceptional implications-a BARFOT study.

BACKGROUND: Bone erosions may appear early or later during rheumatoid arthritis (RA), causing joint damage and functional impairment. However, in some patients erosions do not occur, even after several years of disease. This study evaluates the prevalence, clinical relevance and possible predictors of erosion-free RA. METHODS: Six hundred and eight patients from an early RA cohort (BARFOT) having radiographs of hands and feet at inclusion and after 1, 2, 5 and 8 years were studied. Clinical and functional assessments were performed on all these time-points. RESULTS: In all, 144 patients (24%) did not develop erosions up to 8 years follow-up (Never erosive group), while 464 patients (76%) had erosions on one or more assessments (Ever erosive group). At diagnosis, the patients in the Never erosive group were significantly younger, satisfied fewer ACR criteria, and were less frequently RF- and/or anti-CCP- positive compared with those in the Ever erosive group. The Never erosive patients had consistently more tender joints, lower erythrocyte sedimentation rate (ESR) and, from two years and onwards, fewer swollen joints. Absence of rheumatoid factor (RF) and/or anti-CCP were strong independent predictors for erosion-free disease. The erosion-free patients were less frequently treated with DMARDs and/or prednisolone. CONCLUSIONS: One-quarter of the patients was erosion-free during eight years in this early RA cohort. Erosion-free patients had a less severe disease course as to disease activity and were more often seronegative compared with those with erosive disease. The results suggest that non-erosive RA represents a milder form of RA.

Misdiagnosis of Rheumatoid Arthritis in a Long-Term Cohort of Early Arthritis Based on the ACR-1987 Classification Criteria.

Objective: Correct diagnosis of early rheumatoid arthritis (RA) is essential for optimal treatment choices. No pathognomonic test is available, and diagnosis is based on classification criteria, which can result in misdiagnosis. Here, we examined the differences between actual and misdiagnosed RA cases in a long-term cohort of patients included based on the ACR-1987 classification criteria. Methods: Patients in the BARFOT (Better Anti-Rheumatic PharmacOTherapy) cohort (n=2543) with at least four follow-up visits during the initial 5 years from enrolment were assessed, and a change in diagnosis was reported by the treating rheumatologist. The groups were analysed with respect to the individual classification criteria, antibodies to citrullinated proteins (ACPA), disease activity (DAS28) and radiographic changes from inclusion up to 2 years. Results: Forty-five patients (1.8%) were misdiagnosed (RA-change group). When compared to those in the RA-change group, the patients who kept their diagnosis (RA-keep) were more often RF positive (64% vs 21%, p<0.001) or ACPA positive (59% vs 8%, p<0.001). They were also more likely to fulfil more than four ACR-1987 criteria (64% vs 33%, p<0.001) and to have radiographic changes at inclusion (RA-keep 27% vs RA-change 12%, p=0.04). The groups had a similar evolution of DAS28 and its components as well as of radiological joint destruction. Conclusion: Diagnosis of RA according to the ACR-1987 criteria had a high precision in this long-term cohort. A diagnosis of RA should be re-evaluated in patients who do not fulfil more than four ACR-1987 criteria especially in patients negative for RF.

Higher levels of anti-phosphorylcholine autoantibodies in early rheumatoid arthritis indicate lower risk of incident cardiovascular events.

BACKGROUND: The increased risk of cardiovascular events (CVE) in rheumatoid arthritis (RA) is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. It has been suggested that anti-phosphorylcholine antibodies (anti-PC) of the IgM subclass may have atheroprotective effects. Here, we aimed to investigate the association between levels of IgM anti-PC antibodies with CVE in patients with early RA. METHODS: The study population was derived from the BARFOT early RA cohort, recruited in 1994-1999. The outcome of incident CVE (AMI, angina pectoris, coronary intervention, ischemic stroke, TIA) was tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM. The Kaplan-Meier estimates and Cox proportional hazards regression models were used to compare CV outcome in the groups categorized by baseline median level of IgM anti-PC. RESULTS: In all, 653 patients with early RA, 68% women, mean (SD) age 54.8 (14.7) years, DAS28 5.2 (1.3), 68% seropositive, and without prevalent CVD, were included. During the follow-up of mean 11.7 years, 141 incident CVE were recorded. Baseline IgM anti-PC above median was associated with a reduction in risk of incident CVE in patients aged below 55 years at inclusion, HR 0.360 (95% CI, 0.142-0.916); in males, HR 0.558 (0.325-0.958); in patients with BMI above 30 kg/m2, HR 0.235 (0.065-0.842); and in those who did not achieve DAS28 remission at 1 year, HR 0.592 (0.379-0.924). The pattern of associations was confirmed in the models with AUC IgM anti-PC over 2 years. CONCLUSION: Protective effects of higher levels of innate IgM anti-PC autoantibodies on CVE were detected in younger patients with RA and those at high risk of CVE: males, presence of obesity, and non-remission at 1 year.

Effects of Atorvastatin on T-Cell Activation and Apoptosis in Systemic Lupus Erythematosus and Novel Simulated Interactions With C-Reactive Protein and Interleukin 6.

OBJECTIVE: We study activation of T helper 17 (Th17) and regulatory T (Treg) cells and induction of apoptosis in cells from patients with systemic lupus erythematosus (SLE) compared with controls and effects of atorvastatin and its simulated interactions with other compounds. METHODS: Mononuclear cells from 10 patients with SLE and 10 controls were cultured in conditions that induce Th17 and/or Treg cell polarization and/or apoptosis and were studied by FACScan. Gene expression was determined by quantitative real-time reverse transcription-polymerase chain reaction. Cytokines in plasma were determined by enzyme-linked immunosorbent assay. The Search Tool for Interactions of Chemicals (STITCH) was used to retrieve information regarding the binding properties of atorvastatin. RESULTS: Among patients with SLE, the proportion of Th17 (CD4+ IL17+ ) cells was higher compared with controls after activation, with Th17 or Treg polarizing cytokines, phorbol myristate acetate, and ionomycin. In contrast, Treg cells (CD4+ CD25+ CD127dim/- ) frequencies were lower. CD95 stimulation induced relatively more apoptosis in Treg cells and less in Th17 cells, as compared with controls. Addition of atorvastatin normalized Th17/Treg cell balance and apoptosis induction. Accordingly, the ratio of RORC/FoxP3 decreased in patients with SLE. Interleukin 17 and interleukin 6 (IL-6) levels were increased in patients with SLE. Atorvastatin interacted strongly with C-reactive protein (CRP) and also significantly with IL-6. CONCLUSION: There is a higher proportion of Th17 cells and a lower proportion of Treg cells in patients with SLE after activation. Th17 cells were more resistant than Treg cells to CD95-induced apoptosis in SLE. Atorvastatin normalized these effects. Our findings reveal a novel mechanism behind the imbalance of Th17/Treg cells with implications for treatment in SLE. We determine for the first time simulated interaction between atorvastatin, CRP, and IL-6, implying a novel role of atorvastatin.

Influence of Age and Sex on Disease Course and Treatment in Rheumatoid Arthritis.

OBJECTIVE: More than 50% of patients with rheumatoid arthritis (RA) are >65 years at diagnosis. Age of onset and sex may influence the disease course, outcome and treatment. This study follows a large cohort of patients with early RA to assess contributions of age and sex to disease outcomes. METHODS: Patients from the BARFOT cohort, n=2837 (68% women), were followed for eight years at predefined time points to assess inflammation, function, joint destruction and treatment with disease modifying anti-rheumatic drugs (DMARDs) and glucocorticoids (GC). The patients were divided by sex and age at inclusion (<40, 40-54, 55-69 and ≥70 years). RESULTS: For both sexes, disease activity, function and pain improved over time, significantly more in men than in women in all age groups. In men, those <40 years displayed significantly lower DAS28 compared with all other groups. This group was also the least represented group in the study. The Sharp van der Heijde Score (SHS) increased over time in both sexes and all age groups. Women ≥70 years showed less improvement in disability and the highest progression of SHS mainly due to increased joint space narrowing. Patients <40 years were more likely to receive biological DMARDs, while those ≥70 years more often received only GC treatment. CONCLUSION: There were significant age- and sex-dependent differences in the medical treatment and in outcome of RA 8 years after diagnosis. The differences were most pronounced in men<40 and women ≥70 years, but whether they are due to disease phenotype or treatment is unclear.

Reported disability in relation to observed activity limitation, grip strength and physical function in women and men with rheumatoid arthritis.

BACKGROUND: The self-reported Health Assessment Questionnaire (HAQ) is specifically designed to assess disability in arthritic patients. In many studies women report higher functional disability than men. The reasons for this difference are suggested to be multifactorial. We therefore evaluated functional disability assessed by HAQ in women and men with rheumatoid arthritis (RA) in relation to observed disability, grip force and physical function. METHODS: Patients with RA, 51 women and 49 men, completed the HAQ on three occasions, some weeks apart. Between HAQ1 and HAQ2, all patients performed 17 of the 20 activities (7 domains) included in the HAQ under observation in a specially designed environment, the observed HAQ. During the same day, grip force, measured by GRIPPIT and physical function assessed by the SOFI (Signals of Functional Impairment) index were evaluated. Differences between groups were studied by the chi-square test, Mann-Whitney U test and Wilcoxon Sign Rank test. Correlations were analysed by Spearman rank correlation. Comparisons between repeated measures were performed using Friedman's test. RESULTS: Median (IQR) total HAQ1 score was 0.50 (0.88) for women and 0.25 (0.84) for men, p = 0.038, and the observed HAQ score (7 domains) 0.57 (0.9) for women and 0.43 (0.96) for men, p = 0.292. The correlations between reported HAQ1 score (7 domains) and observed HAQ score were strong, r = 0.860, p < 0.001 in women, and r = 0.820, p < 0.001 in men. For some activities the patients, both women and men, reported lower difficulty than that observed. Women had lower grip force than men, median (IQR), right and left 126 (84) Newton, versus 238 (146), p < 0.001, and there was a negative correlation between grip force and most of the separate activities in HAQ in both genders. SOFI index was similar in women and men, median (IQR) 0 (3.0) versus 0 (2.0), p = 0.277, with a moderate correlation to HAQ. CONCLUSIONS: The results indicate that in well-treated patients with RA the correlations between reported and observed HAQ scores were strong, similarly in women and men. We found no evidence that the patient's opinion was dependent on unawareness of her/his own ability.

Team Rehabilitation in Inflammatory Arthritis Benefits Functional Outcomes Along With Improved Body Composition Associated With Improved Cardiorespiratory Fitness.

OBJECTIVE: We investigated the effect of team rehabilitation in inflammatory arthritis (IA) on body composition and physical function. Further, we examined whether body composition and physical function are associated with disability and cardiorespiratory fitness (CRF). METHODS: The participants were 149 patients (74% women) with chronic arthritis, a mean age of 53 (SD 13) years, and mean disease duration of 21 (SD 13) years. They participated in a 4-week team rehabilitation program and were evaluated at prerehabilitation, and at 3 and 12 months postrehabilitation. Body composition was assessed by bioelectrical impedance analysis and CRF by the Åstrand 6-minute cycle test. ANCOVA with Bonferroni correction and linear mixed models were applied. RESULTS: After 3 and 12 months, there were significant reductions in waist circumference and measures of fat, adjusted for age, sex, and baseline measures. The prevalence of adiposity and central obesity decreased after 12 months. Hand grip strength and timed sit-to-stand (TST) improved together with reduction in Health Assessment Questionnaire (HAQ) and increased VO2max after 3 and 12 months. HAQ reduction over time was associated with prerehabilitation measures of lean mass of legs, hand grip strength, TST, and physical activity, and changes in hand grip strength, physical activity, and sedentary time, but not with changes of body composition. VO2max improvement over time was associated with prerehabilitation BMI, waist circumference, measures of fat and lean mass, changes in BMI, waist circumference, and measures of fat. CONCLUSION: In patients with IA, 4-week team rehabilitation benefited body composition, level of physical functioning, activity, and CRF for up to 12 months. Measures of physical function and activity were linked to HAQ over time, whereas body composition was linked to CRF.

Patients with SLE have higher risk of cardiovascular events and mortality in comparison with controls with the same levels of traditional risk factors and intima-media measures, which is related to accumulated disease damage and antiphospholipid syndrome: a case-control study over 10 years.

OBJECTIVE: SLE is a strong risk factor for premature cardiovascular (CV) disease and mortality. We investigated which factors could explain poor prognosis in SLE compared with controls. METHODS: Patients with SLE and population controls without history of clinical CV events who performed carotid ultrasound examination were recruited for this study. The outcome was incident CV event and death. Event-free survival rates were compared using Kaplan-Meier curves. Relative HR (95% CI) was used to estimate risk of outcome. RESULTS: Patients (n=99, 87% female), aged 47 (13) years and with a disease duration of 12 (9) years, had mild disease at inclusion, Systemic Lupus Erythematosus Diseases Activity Index score of 3 (1-6) and Systemic Lupus International Collaborating Clinics (SLICC) Damage Index score of 0 (0-1). The controls (n=109, 91% female) were 49 (12) years old. Baseline carotid intima-media thickness (cIMT) did not differ between the groups, but plaques were more prevalent in patients (p=0.068). During 10.1 (9.8-10.2) years, 12 patients and 4 controls reached the outcome (p=0.022). Compared with the controls, the risk of the adverse outcome in patients increased threefold to fourfold taking into account age, gender, history of smoking and diabetes, family history of CV, baseline body mass index, waist circumference, C reactive protein, total cholesterol, high-density lipoprotein, low-density lipoprotein, dyslipidaemia, cIMT and presence of carotid plaque. In patients, higher SLICC score and SLE-antiphospholipid syndrome (SLE-APS) were associated with increased risk of the adverse outcome, with respective HRs of 1.66 (95% CI 1.20 to 2.28) and 9.08 (95% CI 2.71 to 30.5), as was cIMT with an HR of 1.006 (95% CI 1.002 to 1.01). The combination of SLICC and SLE-APS with cIMT significantly improved prediction of the adverse outcome (p<0.001). CONCLUSION: In patients with mild SLE of more than 10 years duration, there is a threefold to fourfold increased risk of CV events and death compared with persons who do not have SLE with similar pattern of traditional CV risk factors, cIMT and presence of carotid plaque. SLICC, SLE-APS and subclinical atherosclerosis may indicate a group at risk of worse outcome in SLE.

Low levels of PCSK9 are associated with remission in patients with rheumatoid arthritis treated with anti-TNF-α: potential underlying mechanisms.

BACKGROUND: Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) which raises LDL-levels. In addition, PCSK9 has proinflammatory immunological effects. Here, we investigate the role of PCSK9 in relation to the inflammatory activity in patients with rheumatoid arthritis (RA). METHODS: PCSK9-levels were determined at baseline by ELISA in 160 patients with RA not previously treated with biologics. The patients started anti-TNF-α (adalimumab, infliximab, or etanercept) treatment and were followed-up for 1 year. Disease activity was determined by DAS28. Effects of PCSK9 on cytokine production from macrophages of healthy individuals and synoviocytes from RA patients and inhibition by anti-PCSK9 antibodies were studied in supernatants by ELISA. RESULTS: A significantly lower level of PCSK9 at baseline, p = 0.035, was observed in patients who reached remission within 1 year, defined as DAS28 < 2.6, compared to those not in remission. At 12 months of TNF-α antagonist treatment, the mean DAS28 was reduced but was significantly greater in patients with highest quartile PCSK9 (Q4) compared to those at lowest PCSK9 (Q1) in both crude (p = 0.01) and adjusted analysis (p = 0.004). In vitro, PCSK9 induced TNF-alpha and IL-1beta in macrophages and monocyte chemoattractant protein-1 (MCP1) in synoviocytes. These effects were inhibited by anti-PCSK9 antibodies. CONCLUSIONS: Low levels of PCSK9 at baseline are associated with being DAS28-responder to anti-TNF-α treatment in RA. An underlying cause could be that PCSK9 stimulates the production of proinflammatory cytokines from macrophages and synoviocytes, effects inhibited by anti-PCSK9 antibodies. PCSK9 could thus play an immunological role in RA.

Proprotein convertase subtilisin kexin 9 is associated with disease activity and is implicated in immune activation in systemic lupus erythematosus.

BACKGROUND: Low-density lipoprotein (LDL) levels are increased by proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL receptor. We recently reported that PCSK9 ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL), which is abundant in atherosclerotic plaques and is also associated with cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Here, we investigated the role of PCSK9 in SLE. METHODS: PCSK9 levels were determined by ELISA among SLE patients (N = 109) and age- and sex-matched population-based controls (N = 91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. The effects of PCSK9 and its inhibition by silencing were studied. RESULTS: PCSK9 levels were non-significantly higher among SLE-patients compared to controls but significantly associated with SLE disease activity, as determined by the Systemic Lupus Activity Measure (p = 0.020) or the SLE Disease Activity Index (p = 0.0178). There was no association between PCSK9 levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE patients but not after adjusting for age. OxLDL induced PCSK9 in DCs and DC maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DCs from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC maturation. CONCLUSIONS: PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL promoting DC activation which depends on PCSK9. OxLDL induces PCSK9 - an effect which is higher among SLE patients. PCSK9 could play an unexpected immunological role in SLE.

Similar progression of carotid intima-media thickness in 7-year surveillance of patients with mild SLE and controls, but this progression is still promoted by dyslipidaemia, lower HDL levels, hypertension, history of lupus nephritis and a higher prednisolone usage in patients.

Objective: To compare progression of subclinical atherosclerosis and factors promoting it in patients with SLE and controls. Methods: Consecutive patients with SLE and age-matched, sex-matched population controls from the SLEVIC cohort were assessed at inclusion and after 7 years with standardised data collection and carotid ultrasound. Effect of risk factors on carotid intima-media thickness (cIMT) progression was examined with adjusted linear mixed models. Results: A total of 77 patients and 74 controls, 68% and 61% of the original cohort, completed follow-up. The patients were (mean) 47 years old, 90% were women, and controls were 51 years old, 92% women. Patients had disease duration of (mean) 11 years, mild disease activity and low severity at both assessments. Baseline cIMT did not differ between the groups. An average absolute cIMT progression was 0.009 mm/year in patients and 0.011 mm/year in controls, intergroup difference p=0.9.Of factors at inclusion, dyslipidaemia, lower levels of high-density lipoprotein (HDL) and carotid plaque in patients and controls, and higher systolic blood pressure, total cholesterol:HDL and LDL:HDL ratios and triglycerides in patients were associated with cIMT progression. Of factors at follow-up, hypertension and blood lipids in patients and HDL in controls were significantly associated with cIMT progression. History of lupus nephritis and a higher average dose of prednisolone used since diagnosis were associated with cIMT progression in patients. Associations of risk factors with cIMT progression were stronger in presence of plaques. Conclusion: We observed a statistically comparable progression of cIMT in patients with mild SLE and controls over 7 years, which implies that progression of subclinical atherosclerosis in some patients with SLE could follow that of the general population. Traditional cardiovascular (CV) risk factors, history of lupus nephritis and higher use of corticosteroids promote cIMT progression in SLE. Detection of carotid plaque may add to CV risk stratification.

A Swedish register-based, long-term inception cohort study of patients with rheumatoid arthritis - results of clinical relevance.

PURPOSE: At the end of the twentieth century, the outcome of rheumatoid arthritis (RA) was shown to be unsatisfactory and new therapeutic strategies were introduced. This initiated a register-based long-term study of early RA, the Better Anti-Rheumatic PharmacOTherapy (BARFOT) study. The aims were to evaluate the disease course and to acquire knowledge for improved care. PATIENTS AND METHODS: BARFOT is a multicentre observational study of patients with early RA, consecutively included 1992-2006. The patients are followed in daily practice according to a structured protocol for 15 years and data recorded in a web-based register. Also, through linkage of the BARFOT register to national registers we have acquired information on comorbidity and mortality. RESULTS: In all, 2857 patients have been included and over 80 scientific articles have been published. Phenotypic characteristics at disease onset, i.e. gender, smoking habits and autoantibody profiles have been addressed. The disease course over 15 years was described. Early predictors for persistent disease activity, impaired function, joint damage and co-morbidities have been identified. Treatment strategies have been studied. A randomized sub-study gave strong support for the treatment of recent RA with low-dose prednisolone in combination with disease-modifying anti-rheumatic drug. Furthermore, the impact of lifestyle factors, such as smoking, alcohol consumption, body weight and physical activity has been addressed. CONCLUSION: A register-based study like BARFOT has provided a basis for optimal long-term management of patients with RA. In addition, the register has made it possible to perform a diversity of studies of RA addressing various issues of major relevance to the patients.

Widespread pain and pain intensity in patients with early rheumatoid arthritis. A cross-sectional comparison between smokers and non-smokers.

AIM: The aim was to investigate if smoking status at time for diagnoses of rheumatoid arthritis was associated with pain intensity or pain spread. DESIGN: A cross-sectional study conducted in 2012-2013. METHODS: Seventy-eight patients, of whom 16 were current smokers and 62 never or previous smokers, with newly diagnosed rheumatoid arthritis were assessed as to pain intensity, widespread pain and disease activity. RESULTS: Of the participants, 56% had unacceptable pain, 77% had spread pain and 28% had chronic widespread pain. There were no differences in pain intensity, widespread pain or chronic widespread pain between smoking status groups. However, there was a positive association between pain intensity and disease activity, r = 0.52. CONCLUSION: In this study, patients with early rheumatoid arthritis had a high-frequency unacceptable pain and wide spread pain, irrespective of smoking status. However, we cannot exclude that the inflammatory-associated pain overshadowed a possible negative effect of smoking.

Anti-citrullinated protein antibodies are associated with osteopenia but not with pain at diagnosis of rheumatoid arthritis: data from the BARFOT cohort.

BACKGROUND: Anti-citrullinated protein antibodies (ACPA) have been suggested to have a potential role in both bone loss and pain in rheumatoid arthritis (RA), based on studies in vitro and in animal models. Here we addressed if anti-cyclic citrullinated (anti-CCP) antibodies were associated with osteopenia or pain in patients with RA, at the time for diagnosis. METHODS: Baseline data from the BARFOT (Better Anti-Rheumatic PharmacOTherapy) cohort, which consists of patients with RA with a disease duration of 1 year or less, were analyzed. To be included, they should have been assessed by anti-CCP, dual-energy X-ray absorptiometry (DEXA) of lumbar spine and hip, and/or digital X-ray radiogrammetry (DXR) of the metacarpal bones. Osteopenia was defined as a z-score < - 1 SD. Pain VAS > 40 mm, was defined as patient unacceptable pain. Multiple logistic regression analyses were performed to assess whether anti-CCP was independently associated with osteopenia or unacceptable pain. RESULTS: Of the 657 patients, 65% were women, 58% were anti-CCP positive, 37% had osteopenia in the lumbar spine, and 29% had osteopenia in the hip. Sixty-one percent had unacceptable pain at diagnosis. Patients positive for anti-CCP had significantly more frequently osteopenia in the femoral neck and Ward's triangle compared with anti-CCP-negative patients (p = 0.016 and 0.003, respectively). This difference was found in men at any anti-CCP titer, but in women, osteopenia in these hip locations was found only in those with high anti-CCP titers (> 500 IU/ml). Anti-CCP was not associated with osteopenia in the lumbar spine or the metacarpal bones. In multiple logistic regression analyses, anti-CCP was independently associated with osteopenia in the femoral neck and/or Ward's triangle but not with unacceptable pain. Instead, inflammatory variables were independently associated with unacceptable pain. CONCLUSION: These data show that in patients with early RA, anti-CCP positivity was independently associated with osteopenia in the femoral neck and/or Ward, but not in the lumbar spine. In our patients, we could not confirm a recently suggested association between anti-CCP antibodies and pain. Further studies are necessary to explore the possible clinical relevance of interactions between ACPA, bone, and pain found in vitro and in animal models.

Obesity is a strong predictor of worse clinical outcomes and treatment responses in early rheumatoid arthritis: results from the SWEFOT trial.

OBJECTIVES: The aim of this paper was to analyse the impact of obesity, in addition to known predictors, on disease outcome in early rheumatoid arthritis (RA). METHODS: Body mass index (BMI) was available in 260 patients from the Swedish pharmacotherapy trial (SWEFOT). Differences in disease activity (DAS28), functional impairment (HAQ), pain (Visual Analogue Scale, VAS-pain) and radiographic damage were evaluated over 24 months between BMI categories (obese BMI >30, n=43; overweight BMI=25-29.9, n=74; normal BMI <25, n=143) using non-parametric testing. Predictors of European League Against Rheumatism non-remission (DAS28 ≥2.6) at 24 months of follow-up were evaluated using binary univariate and multivariate logistic regression. RESULTS: Obesity at baseline was associated with worse continuous-scale clinical outcomes over 24 months (DAS28, HAQ and VAS-pain at last visit: obese vs normal: p<0.001; obese vs overweight: p<0.05). Furthermore, obese patients compared with non-obese patients had significantly greater odds of non-remission at 24 months (adjusted OR (aOR) 5.2; 95% CI 1.8 to 15.2). Other independent predictors were female sex (aOR 2.6; 95% CI 1.1 to 5.8), current smoking (aOR 2.6; 95% CI 1.1 to 6.3) and HAQ (per-unit increase, aOR 1.9; 95% CI 1.1 to 3.4). The pattern was similar among seropositive and seronegative patients; and in the subgroups of methotrexate responders and patients randomised at 3 months to add-on of sulfasalazine+hydroxychloroquine, although not significant with add-on of infliximab. Obesity had no independent association to radiographic progression. CONCLUSIONS: In this early RA trial reflecting today's standard treatment, obesity, in addition to sex, smoking and functional impairment strongly lowered the chance of attaining good clinical outcomes, including remission, today's treatment goal. This highlights the importance of considering lifestyle modification as one of the cornerstones of RA care. TRIAL REGISTRATION NUMBER: NCT00764725; Post-results. WHO database at the Karolinska University Hospital: CT20080004.

Patients with Early Rheumatoid Arthritis in the 2000s Have Equal Disability and Pain Despite Less Disease Activity Compared with the 1990s: Data from the BARFOT Study over 8 Years.

OBJECTIVE: To compare outcomes over the first 8 years in patients with early rheumatoid arthritis (RA) recruited in the 1990s and the 2000s, with a special focus on functional disability and its possible predictors. METHODS: Data were acquired from 1938 patients with early RA (American College of Rheumatology 1987 criteria) included in the BARFOT study, who had completed the 8-year followup. The patients were divided into 2 cohorts: cohort 1 (n = 928, 68% women) included from 1992 to 1999 and cohort 2 (n = 1010, 70% women) included from 2000 to 2006. Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28), visual analog scale pain, and radiographs of hands and feet scored by the van der Heijde modified Sharp method were assessed during the 8 years. Longitudinal data analyses were performed using a generalized linear model. RESULTS: Despite more active medical treatment during the 2000s, the courses of HAQ and pain showed no difference between the cohorts during followup, in either women or in men, with significantly higher levels in women compared with men. However, as expected, disease activity decreased more over time in cohort 2 compared with cohort 1, for both sexes, and women in cohort 2 had less radiographic progression compared with cohort 1. HAQ was associated with DAS28, pain, radiological scores, and sex in both cohorts, and in cohort 2 also with age and smoking. CONCLUSION: Patients included in the 2000s had lower disease activity, but not less activity limitation and pain over 8 years of followup despite more active treatment. Pain, aging, and smoking might explain why patients included in the 2000s still had the same disability levels as those included in the 1990s.

Smoking is associated with the concurrent presence of multiple autoantibodies in rheumatoid arthritis rather than with anti-citrullinated protein antibodies per se: a multicenter cohort study.

BACKGROUND: The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies. METHODS: A population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression. RESULTS: In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32-6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78-1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04-1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53-2.73). CONCLUSIONS: Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.