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.

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.

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.

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.

Bone mineral density and carotid atherosclerosis in systemic lupus erythematosus: a controlled cross-sectional study.

INTRODUCTION: As osteoporosis is reported to be associated with atherosclerosis in the general population we examined the relationship between bone mass and carotid measurements in patients with systemic lupus erythematosus (SLE) and controls, and possible links between them in SLE. METHODS: In a cross-sectional study, 111 SLE-patient were compared with 111 age- and sex-matched controls, mean age 48.7(12.9) years, 89% were women, of which 51% postmenopausal. Carotid intima media thickness (cIMT), carotid plaque occurrence and echogenicity were determined by B-mode ultrasound and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). RESULTS: BMD and cIMT were inversely associated both in patients and controls. Patients, but not controls, with carotid plaque had higher cIMT at low BMD than at normal BMD, p = 0.010. Logistic regression indicated more than doubled odds ratio (OR) of carotid plaque in patients, particularly in post-menopausal women, than in controls in relation to all BMD measurements. For low BMD at hip, significant increased OR for echolucent plaque was shown for patients compared with controls. In patients, significant impact of age, body mass index, smoking, systolic blood pressure, blood lipids, diabetes mellitus, impaired renal function, low levels of complement C3 and C4, history of nephritis, SLE-damage index and ever use of antimalarial was found for association between BMD and higher cIMT and carotid plaque. In multivariate regression, low C4 was independent contributor to association between total BMD and upper cIMT tertile, accounted for OR (95% confidence interval) of 3.2 (1.03-10.01), and also for association with bilateral carotid plaque, OR of 4.8 (1.03-22.66). The contribution of low C4 for the association between BMD and carotid atherosclerosis was enhanced within the second and third tertiles of total BMD. CONCLUSION: This study is the first to demonstrate inverse association between BMD and carotid measurements in both SLE-patients and controls. Our results suggest that SLE-patients may suffer higher burden of (sub)clinical atherosclerotic disease, especially presence of both echolucent and echogenic plaque, than controls with the same bone mineral status. Low complement C4 seems to play an important role in earlier development of carotid atherosclerosis already within (sub)normal ranges of total BMD in patients.

Smoking in combination with antibodies to cyclic citrullinated peptides is associated with persistently high levels of survivin in early rheumatoid arthritis: a prospective cohort study.

INTRODUCTION: High levels of the oncoprotein survivin may be detected in the majority of patients with early rheumatoid arthritis (RA). Survivin is a sensitive predictor of joint damage and persistent disease activity. Survivin-positive patients are often poor responders to antirheumatic and biological treatment. The aim of this study was to investigate the reproducibility of survivin status and its significance for clinical and immunological assessment of RA patients. METHODS: Survivin levels were measured in 339 patients from the Better Anti-Rheumatic FarmacOTherapy (BARFOT) cohort of early RA at baseline and after 24 months. The association of survivin status with joint damage (total Sharp-van der Heijde score), disease activity (Disease Activity Score based on evaluation of 28 joints (DAS28)), functional disability (Health Assessment Questionnaire (HAQ)), and pain perception (Visual Analogue Scale (VAS)) was calculated in the groups positive and negative for survivin on both occasions, and for the positive-negative and negative-positive groups. RESULTS: In 268 patients (79%) the levels of survivin were similar at baseline and after 24 months, 15% converted from survivin-positive to survivin-negative, and 5% from survivin-negative to survivin-positive. A combination of smoking and antibodies against cyclic citrullinated peptides (aCCP) predicted persistently (baseline and 24 months) high levels of survivin (odds ratio 4.36 (95% CI: 2.64 to 7.20), P < 0.001), positive predictive value 0.66 and specificity 0.83). The independent nature of survivin and aCCP was demonstrated by statistical and laboratory analysis. Survivin positivity on both test occasions was associated with the progression of joint damage, significantly higher DAS28 and lower rate of remission at 24 and 60 months compared to negative-negative patients. Survivin status was less associated with changes in HAQ and VAS. CONCLUSIONS: Survivin is a relevant and reproducible marker of severe RA. Persistently high levels of survivin were associated with smoking and the presence of aCCP and/or RF antibodies and predicted persistent disease activity and joint damage.

Low-dose prednisolone in early rheumatoid arthritis inhibits collagen type I degradation by matrix metalloproteinases as assessed by serum 1CTP--a possible mechanism for specific inhibition of radiological destruction.

OBJECTIVE: To study the effects of low-dose prednisolone on the osteoclast-regulating proteins osteoprotegerin (OPG) and RANK ligand (RANKL) and on markers of bone resorption, 1CTP generated by MMPs and CTX-1 generated by cathepsin K, in patients with early RA in relation to inflammation and joint destruction. METHODS: In 225 patients, who at the start of the first DMARD had been randomized to 7.5 mg prednisolone daily for 2 years, the P-group, or no prednisolone, the NoP-group, OPG and RANKL were analysed at 0-24 months and 1CTP and CTX-1 at 0-12 months. Radiographs of hands and feet were assessed at 0, 1 and 2 years using the modified Sharp-van der Heijde score and radiological progression defined as increase in total Sharp score above 5.8. Data were analysed with a mixed linear model and by the GENMOD procedure. RESULTS: In the P-group, RANKL and the ratio OPG/RANKL were stable between baseline and 24 months, whereas in the NoP-group, RANKL increased and the ratio OPG/RANKL decreased. CTX-1 decreased significantly more in the P-group. 1CTP decreased over time in both groups, but more in the P-group, P < 0.001, a difference also present in the subgroups of patients in remission. The decrease in 1CTP was associated with less radiological progression after 2 years and displayed a significant interaction with treatment. CONCLUSION: Low-dose prednisolone may inhibit progression of joint destruction by interfering with MMP activity, seen as a marked decrease in 1CTP, as well as by impairing osteoclast activation, shown by a stable OPG/RANKL ratio.

Association of obesity with worse disease severity in rheumatoid arthritis as well as with comorbidities: a long-term followup from disease onset.

OBJECTIVE: To determine the association of obesity, defined as a body mass index (BMI) ≥30 or ≥28 kg/m(2) or by waist circumference (WC), with disease activity and severity, as well as its relationship to comorbidities in rheumatoid arthritis (RA). METHODS: The study population comprised 1,596 patients with early RA (mean ± SD age 55.6 ± 14.6 years, 67.8% women) who had been included in the Better Anti-Rheumatic Farmacotherapy observational study from 1992-2006. In 2010, data on lifestyle factors and comorbidities were collected through a postal questionnaire, answered by 1,391 patients. Clinical outcomes were the Disease Activity Score in 28 joints, sustained remission, physical function (Health Assessment Questionnaire [HAQ]), and pain and global health assessed on a visual analog scale, as well as predefined comorbidities. RESULTS: After a mean ± SD of 9.5 ± 3.7 years, the mean ± SD BMI had increased from 25.4 ± 4.2 to 26.0 ± 4.5 kg/m(2) (P = 0.000). The prevalence of BMI ≥30 kg/m(2) was 12.9% at baseline and 15.8% at followup. In multivariable regression, BMI and obesity, defined as a BMI ≥30 or ≥28 kg/m(2) , at both inclusion and the time of the survey were independently associated with higher disease activity, fewer patients in sustained remission, higher HAQ score, more pain, and worse general health. Also, BMI and obesity independently conferred to higher odds for being diagnosed with hypertension, diabetes mellitus, and chronic pulmonary disease. Further, BMI and WC were independently associated with angina pectoris/acute myocardial infarction/coronary revascularization. In contrast, none of the examined obesity variables was associated with the prevalence of stroke or transient ischemic attack. Lifestyle changes during the observational period, such as quitting smoking or diet change, had no impact on the outcomes. CONCLUSION: Obesity was associated with worse RA disease outcomes and a higher prevalence of comorbidities. Body measurements are recommended to improve prediction of the disease course.

Effect of biological therapy on levels of atheroprotective antibodies against phosphorylcholine and apolipoproteins in rheumatoid arthritis - a one year study.

OBJECTIVES: To examine how treatment of rheumatoid arthritis (RA) with anti-tumour necrosis factor alpha antagonists (anti-TNF) and B-cell targeting rituximab influences novel markers of atherosclerosis and inflammation, such as atheroprotective natural IgM antibodies against phosphorylcholine (anti-PC), oxidised low-density lipoprotein (oxLDL) and apolipoproteins. METHODS: In a prospective study 215 patients with RA were enrolled of whom 85.6% were seropositive, aged 57.9 ± 12.4 years, with mean disease duration 8.5 (5-15) years. 162 patients were treated with anti-TNF and 53 with rituximab for one year. The patients were assessed and blood sampled at 0, 3, 6 and 12 months. IgM anti-PC and oxLDL were determined by ELISA and apolipoproteins by immunoturbidimetry. RESULTS: IgM anti-PC increased by 26% during anti-TNF treatment, p<0.001, while decreased by 14% on rituximab, p=0.023, after 12 months of treatment. Patients in remission after 12 months, DAS28<2.6, had higher baseline anti-PC levels compared with those not in remission in both anti-TNF, p=0.007, and rituximab-treated subjects, p=0.041. In both treatment groups, levels of oxLDL increased temporarily at three months but apoA1 improved throughout the study. This effect was inversely correlated with changes in disease activity. The apoB and apoB/apoA1-ratio remained stable throughout the whole study period. CONCLUSIONS: Anti-TNF treatment demonstrated a favourable long-term effect on anti-PC levels. Low levels of IgM anti-PC may identify immune-deficient state and predict inferior therapy response. Biological therapies increased the level of the anti-atherogenic lipid apoA1. The impact of these effects on future CVD events deserves further studies.

Longitudinal levels of apolipoproteins and antibodies against phosphorylcholine are independently associated with carotid artery atherosclerosis 5 years after rheumatoid arthritis onset--a prospective cohort study.

OBJECTIVE: RA is associated with premature atherosclerosis. Here, we determined the associations of apolipoproteins and immunoglobulin M (IgM) antibodies against phosphorylcholine (anti-PC) with carotid artery atherosclerosis in a prospective cohort of patients with early RA. METHODS: In all 114 patients, age 50.6 (11.2) years, 68.4% women, with recent RA (<12 months after symptoms onset) were included and assessed at 0, 3, 12, 24 and 60 months after RA diagnosis. At the same time points, apolipoproteins were determined by immunoturbidimetry, and IgM anti-PC by ELISA. Carotid intima-media thickness (cIMT) (common carotid) and occurrence of plaques (common, internal and external carotids) were the principal study outcomes, which were examined with high-resolution B-mode ultrasonography after 5 years of RA disease. Mixed linear modelling and generalized estimating equations (GEEs) were used for longitudinal statistical analyses. RESULTS: Multivariate regression analyses showed that age, male gender, smoking (ever) and history of cardiovascular disease (CVD), hypertension or diabetes mellitus, but no other baseline variables, had independent associations with cIMT (P < 0.05). Plaque detection was positively associated with age and smoking (ever). After adjustment, a longitudinal approach demonstrated an independent negative prediction of cIMT by apoA1 (P = 0.047), but a positive by apoB/apoA1 ratio (P = 0.030). Higher levels of pro-atherogenic apolipoproteins over time, apoB and apoB/apoA1 ratio, and low anti-PC tertile were independently associated with enhanced detection of bilateral carotid plaque (P = 0.002, 0.026 and 0.000, respectively). Both baseline and longitudinal levels of inflammatory/disease-related factors failed to show significant associations with the study outcomes. CONCLUSION: Apolipoproteins and anti-PC may have independent roles in subclinical atherosclerosis in patients with RA.

Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections.

OBJECTIVE: Late-onset neutropenia following rituximab therapy is a well-recognized side effect in lymphoma patients, but only a few cases of late-onset neutropenia have been reported in patients with autoimmune disorders. The purpose of this study was to define the incidence, clinical features, and some of the underlying mechanisms of late-onset neutropenia in relation to rituximab use in several rheumatic diseases. METHODS: We conducted a retrospective analysis of a cohort of 209 consecutive patients with rheumatic diseases who had been treated with rituximab at a university hospital between June 2003 and March 2009. RESULTS: Eleven patients with late-onset neutropenia were identified. The highest incidence was observed in granulomatosis with polyangiitis (Wegener's) and systemic lupus erythematosus patients (23% and 20%, respectively), whereas the incidence in rheumatoid arthritis patients was 3%. The median time to onset of neutropenia was 102 days (range 40-362 days) and coincided with the entire period of B lymphocyte depletion; this depletion was more pronounced in patients with late-onset neutropenia (P = 0.002) than in a control group of 20 matched patients without late-onset neutropenia. Serum IgM levels decreased during the same time and to a significantly greater amount in patients with late-onset neutropenia than in controls (P = 0.027). No patient with late-onset neutropenia displayed specific antineutrophil antibodies. Seven patients were hospitalized because of infections (6 with sepsis and 1 with febrile neutropenia) that required intravenous antibiotics. Six were treated with granulocyte colony-stimulating factor. CONCLUSION: In patients treated with rituximab for rheumatic diseases, late-onset neutropenia is a clinically significant adverse event associated with marked B lymphocyte depletion and severe infections. The incidence of late-onset neutropenia appears to vary with autoimmune disease type.

Low level of physical activity in women with rheumatoid arthritis is associated with cardiovascular risk factors but not with body fat mass--a cross sectional study.

BACKGROUND: As many patients with rheumatoid arthritis (RA) have increased fat mass (FM) and increased frequency of cardiovascular diseases we evaluated if total physical activity (MET-hours) had impact on body composition and cardiovascular risk factors in women with RA. METHODS: Sixty-one out-ward RA women, 60.8 (57.3-64.4) years, answered a self-administered questionnaire, to estimate total daily physical activity during the previous year. Physical activity level was given as metabolic equivalents (MET) × h/day. Diet content was assessed by a food frequency questionnaire and body composition by whole-body dual-energy X-ray absorptiometry. Blood lipids and antibodies against phosphorylcholine (anti-PC) were determined. RESULTS: Forty-one percent of the women had BMI > 25, 6% were centrally obese and 80% had FM% > 30%. The median (IQR) total physical activity was 40.0 (37.4-47.7), i.e. the same activity level as healthy Swedish women in the same age. Total physical activity did not significantly correlate with disease activity, BMI or FM%. Disease activity, BMI and FM% did not differ between those in the lowest quartile of total physical activity and those in the highest quartile. However, the women in the lowest quartile of physical activity had lower HDL (p = 0.05), Apo A1 (p = 0.005) and atheroprotective natural anti-PC (p = 0.016) and higher levels of insulin (p = 0.05) and higher frequency of insulin resistance than those in the highest quartile. Women in the lowest quartile consumed larger quantities of saturated fatty acids than those in the highest quartile (p = 0.042), which was associated with high oxidized low-density lipoprotein (oxLDL). CONCLUSION: This cross sectional study demonstrated that RA women with fairly low disease activity, good functional capacity, high FM and high frequency of central obesity had the same total physical activity level as healthy Swedish women in the same age. The amount of total physical activity was not associated with functional capacity or body composition. However, low total physical activity was associated with dyslipidemia, insulin resistance, low levels of atheroprotective anti-PC and consumption of saturated fatty acids, which is of interest in the context of increased frequency of cardiovascular disease in RA.

Comprehensive rehabilitation of patients with rheumatic diseases in a warm climate: a literature review.

OBJECTIVE: To present the evidence for the efficacy of comprehensive rehabilitation in a warm climate of patients with a wide variety of rheumatic diseases. METHODS: A systematic review of the literature was undertaken, searching in PubMed, Cinahl, Pedro, SweMed and Embase from 1970 to 2010, and using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation system) criteria. RESULTS: Six studies met the inclusion criteria. For patients with rheumatoid arthritis, moderate evidence was found for reduction of disease activity, pain, fatigue, and global disease impact. The evidence was also moderate that comprehensive rehabilitation in a warm climate did not improve fitness or reduce activity limitation beyond levels reached by rehabilitation in Scandinavia. Among patients with ankylosing spondylitis, low evidence was found for reduction of disease activity, pain, joint range of motion, activity limitation, and global disease impact. In groups with mixed rheumatic diagnoses, low evidence was found for reduction of pain, activity limitation, global disease impact and improved health-related quality of life. No studies on psoriatic arthritis, osteoarthritis, fibromyalgia or osteoporosis were found. CONCLUSION: Well-designed studies to validate and improve the low-to-moderate evidence found for the efficacy of comprehensive rehabilitation in a warm climate among patients with inflammatory rheumatic disease are greatly needed.

Increased expression of proto-oncogene survivin predicts Joint destruction and persistent disease activity in early rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is characterized by an uncontrolled spread of destructive joint inflammation resembling malignancy. Epidemiological studies have established strong correlation between inflammation and predisposition for cancer. Here we assess the predictive role of the circulating proto-oncogene survivin for clinical and radiological outcome of early RA. PATIENTS AND METHODS: Serum survivin was measured by sandwich ELISA in 651 patients with early RA (mean duration 6 months). X-rays of hands and feet were prospectively obtained at base-line and after 1, 2, and 5 years and evaluated for the presence of bone destruction by a modified Sharp method. The predictive value of survivin for radiological destruction was calculated using multivariate regression models including antibodies against cyclic citrullinated peptides (aCCP) and rheumatoid factor (RF). Remission was assessed by the EULAR (European League Against Rheumatism) criteria and by criteria proposed by Mäkinen. RESULTS: At base-line, 391 patients (60%) had high levels of survivin. Radiological progression at 5 years was significantly more frequent (P= 0.001) among survivin-positive patients than among survivin-negative. Survivin positivity predicted radiological progression independently of aCCP and RF. The positive predictive value of survivin was proved both in the group of patients with and in the group without erosions at base-line. The combination of positive tests for both survivin and aCCP had the highest prediction for radiological progression (positive predictive value 0.75). Additionally, a positive test for survivin was an independent predictor of not being in remission. CONCLUSION: Detection of survivin in early RA predicted joint destruction and failure of achieving remission after 5 years in patients with early RA.

Rheumatoid cachexia, central obesity and malnutrition in patients with low-active rheumatoid arthritis: feasibility of anthropometry, Mini Nutritional Assessment and body composition techniques.

BACKGROUND AND AIMS: The concurrent decrease in fat free mass (FFM) and increase in fat mass (FM), including central obesity, in patients with rheumatoid arthritis (RA) may be related to increased cardiovascular morbidity as well as to functional decline. The objectives of this study were to evaluate body composition and nutritional status in patients with RA and the feasibility of bioelectrical impedance (BIA) to detect rheumatoid cachexia. METHODS: Eighty RA outpatients (76% women), mean age 61 (range 22-80) years and with mean disease duration of 6 (range 1-52) years, were assessed by body mass index (BMI), waist circumference (WC), whole-body dual-energy X-ray absorptiometry (DXA), BIA and the Mini Nutritional Assessment (MNA). RESULTS: Fat free mass index (FFMI; kg/m(2)) was low in 26% of the women and in 21% of the men. About every fifth patient displayed concomitant low FFMI and elevated fat mass index (FMI; kg/m(2)), i.e. rheumatoid cachexia. BMI and MNA were not able to detect this condition. Sixty-seven percent had increased WC. Reduced FFM was independently related to age (p = 0.022), disease duration (p = 0.027), ESR (p = 0.011) and function trendwise (p = 0.058). There was a good relative agreement between DXA and BIA (FM r (2) = 0.94, FFM r (2) = 0.92; both p < 0.001), but the limits of agreement were wide for each variable, i.e. for FM -3.3 to 7.8 kg; and for FFM -7.9 to 3.7 kg. CONCLUSION: Rheumatoid cachexia and central obesity were common in patients with RA. Neither BMI nor MNA could detect this properly. There was a good relative agreement between DXA and BIA, but the limits of agreement were wide, which may restrict the utility of BIA in clinical practice.

Rheumatoid cachexia is associated with dyslipidemia and low levels of atheroprotective natural antibodies against phosphorylcholine but not with dietary fat in patients with rheumatoid arthritis: a cross-sectional study.

INTRODUCTION: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD) independent of traditional risk factors. The aim of this study was to analyze the associations between diet, body composition, lipids and atheroprotective natural antibodies against phosphorylcholine (anti-PC) in patients with RA. METHODS: A total of 80 RA patients (76% women), mean age (standard deviation (SD)) 61.4 (12) years and median disease duration of 6 years, were assessed by food frequency questionnaire (FFQ), fatty acid profile in adipose tissue and whole-body dual energy x ray absorptiometry (DXA). Rheumatoid cachexia was defined as fat free mass index below the 25th percentile and fat mass index above the 50th percentile of a reference population. Blood lipids, oxidized low-density lipoprotein (oxLDL) and anti-PC levels were determined. RESULTS: The mean body mass index for the women and men was 25.0 and 27.0, respectively. Central obesity was found in 57% of the women (waist circumference >80 cm) and in 89% of the men (waist circumference >94 cm). In all, 18% of the women and 26% of the men had rheumatoid cachexia. These patients had significantly higher total cholesterol (P < 0.033), LDL (P < 0.029), and trendwise oxLDL (P = 0.056) as well as lower anti-PC IgM (P = 0.040), higher frequency of hypertension (69%) and metabolic syndrome (25%) than those without. The patients reported a high dietary intake of saturated fat, which partly correlated with fatty acid composition in adipose tissue and significantly with disease activity. However, patients with or without cachexia did not differ with respect to dietary fat intake or intake of Mediterranean-like diet. Additionally, patients on a Mediterranean-like diet had high levels of anti-PC (P < 0.001). CONCLUSIONS: About one in five patients with low-active RA displayed rheumatoid cachexia. This condition was associated with high levels of LDL cholesterol, low levels of atheroprotective anti-PC and high frequency of hypertension, which is of interest in the context of CVD in RA. The cachexia could not be related to diet fat intake. However, patients on a Mediterranean-like diet had high anti-PC levels in spite of similar frequency of cachexia. High anti-PC levels may provide some protection against CVD.