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OBJECTIVE: To evaluate a possible systemic effect of joint inflammation in contrast to skin disease only, by measuring IL-6 and IL-2sRalpha. METHODS: Two hundred and nineteen patients (111 male / 108 female, age 50.4+/-14.5 yrs (mean+/-SD)) with psoriasis were clinically and laboratory examined. 134 patients had inflammatory joint manifestations defined as peripheral arthritis and/or axial disease, of whom 37 had measurable inflammation, defined as ESR >25 mm/h and/or CRP >15 mg/L. RESULTS: Interleukin-6 was significantly higher in patients with joint disease and measurable inflammation ((median, Q1-Q3) 4.07, 0.92-14.60), and in patients without measured inflammation (1.22, 0.70-3.46), compared to patients with skin disease only (0.70, 0.70-1.73, p<0.001 and p=0.002 respectively). The difference between the two groups of patients with inflammatory joint manifestations was significant (p=0.001). The levels of IL-6 correlated with the actual number of joints affected with arthritis (p<0.001; rs=0.248), ESR (p<0.001; rs=0.459), CRP (p<0.001; rs=0.314) and IL-2sRalpha (p=0.002; rs=0.210). The levels of IL-2sRalpha. did not differ between the 3 groups. CONCLUSION: In this study, IL-6 was significantly higher in patients with psoriasis and inflammatory joint disease with or without routine measurable inflammatory activity compared with patients having psoriasis of the skin. We found that patients with psoriasis and joint inflammation may have systemic effects that could be captured by serum measurements of IL-6. Soluble IL-2Ralpha was not a marker of inflammation in this study.

OBJECTIVE: The aim of this study was to investigate whether homocysteine is linked to atherothrombotic (AT) events in patients with rheumatoid arthritis (RA). METHODS: Analysis of homocysteine (Hcy) levels was carried out in 235 consecutive RA patients. They were followed-up for 6.5 years or until death, with analysis of AT risk factors and the type and length of DMARD and corticosteroid treatment. The disease history before inclusion was collected. Six categories of AT events were defined. In addition, the diagnosis of the patients at follow-up was co-analyzed with the nationwide population-based Swedish Inpatient Register and Death Register to certify all events. RESULTS: The Hcy level was found to be higher in males (p<0.05) and increased with age (p<0.001). Patients with folic acid supplementation had significantly lower levels, while those on corticosteroids had higher levels. High Hcy levels predicted AT events (n=48) during a 6.5-year follow-up adjusted for age and male sex in a logistic regression analysis. CONCLUSION: In this study, RA patients on folic acid had lower Hcy levels. High Hcy levels (in addition to age, sex and diabetes) predicted AT event prospectively.

Objective

One of the main goals of the European Autoimmunity Standardisation Initiative (EASI) is the harmonisation of test-algorithms for autoantibodies related to systemic autoimmune rheumatic diseases (SARD).

Methods

A questionnaire was used to gather information on methodology, interpretation, and the algorithm for detection of anti-nuclear antibodies (ANA) in relation to their antigen-specificity. The questionnaire was sent to 1200 laboratories in 12 European countries.

Results

The response rate was 47.2%. The results reveal not only apparent differences between countries, but also within countries.

Conclusion

Awareness of these differences may as such already stimulate harmonisation, but the observed differences may also direct recommendations that may further contribute to achieving the EASI goal of harmonisation of autoimmune diagnostics for SARD.

OBJECTIVES: To investigate the relationship between biomarkers known to be involved in both chronic inflammation and subclinical atherosclerosis, as measured by carotid intima media thickness (cIMT), in patients with RA compared to controls.

METHODS: Between 2000 and 2004, all patients under 60 years of age with newly diagnosed RA in the northern region of Sweden were invited to participate in this study. Measurements of cIMT were undertaken at inclusion (T0), after five years of follow-up (T5) and after eleven years of follow-up (T11). Patients were clinically assessed and blood was drawn for analysis of biomarkers.

RESULTS: In patients with RA (n=54), linear regression models showed that cIMT at T11 was associated with levels of GDF-15 at T5 and T11, but not with baseline levels. GDF-15 was strongly associated with age. At T11, mean level of GDF-15 was elevated compared to controls. Levels of adiponectin, MCP-1, cathepsin S, endoglin and IL-6 were higher in patients with RA compared to controls, but showed no association with cIMT. In multivariable linear regression models with cIMT at T11 as dependent variable, change in GDF-15 from T0 to T11 was associated to an increase in cIMT at T11. Adjusting for systolic blood pressure and age respectively rendered this association statistically non-significant,

CONCLUSIONS: Among these patients with RA GDF-15 was associated to cIMT after 11 years of follow-up. GDF-15 should be a biomarker of interest in future research, to further understand its role in the accelerated atherogenesis in patients with RA.

Introduction/Aims: Intestinal dysbiosis may be involved in the pathogenesis of ankylosing spondylitis (AS). We aimed to define differences in the gut microbiota composition between patients with AS, ulcerative colitis (UC) and healthy controls (HC) and determine the relations between gut microbiota, fecal calprotectin (FCal) and disease related variables in AS.

Methods: Fecal microbiota was analyzed in patients with AS(N=150), UC(N=18) and HC(N=17) using 16S rRNA sequence technique in a targeted approach. Fecal bacterial abundance and profile was also compared with a healthy reference group creating a Dysbiosis Index score (DI 1-5). The AS patients were assessed with questionnaires, back-mobility tests, FCal, ESR and CRP.

Results: Principal component analysis showed highly separate clustering of the microbiota in stool samples from patients with AS, UC and HC. We found an expansion of Proteobacteria and a contraction of Bacteroidetes and Lachnospiraceae in AS. Dysbiosis (defined as DI≥3) was found in 88% of AS and an elevated DI correlated with increased FCal (rS=0.303; p<0.001). Samples from AS patients with FCal<50 (n=57) and >200 mg/kg (n=36) clustered separately in multivariate analysis. The patients with a FCal>200 mg/kg had lower abundance of bacteria with anti-inflammatory effects such as Faecalibacterium prausnitzii and Clostridium and higher abundance of various types of Streptococci. No clear association was found between the overall fecal microbiota composition and HLAB-27 status, disease activity, function or medication.

Conclusions: The fecal microbiota signature differed greatly between patients with AS, UC and HC. An increased FCal, suggestive of intestinal inflammation, was associated with aberrations in the microbiota composition and increased dysbiosis.

Background: Knowledge about health related quality of life (HRQoL) in Ankylosing spondylitis (AS) is limited. The aims of this study were to assess HRQoL by short form-36 (SF-36) in a cohort of patients with AS compared with controls and to examine associations between SF-36 and spinal radiographic changes, physical function, disease activity and demographic data overall and stratified by sex.

Method: A cohort of patients with AS were assessed with spinal radiographs for mSASSS, BASMI, BASFI, ASDAS-CRP, BASDAI, BASG and SF-36. Each patient’s SF-36 results were compared with 5 age- and sex-matched persons (n=1055) from the SF-36 Swedish normative population database. Associations between SF-36 physical component summary (PCS) and mental component summary (MCS) scores and disease related and demographic factors were investigated with univariate and multiple logistic regression analyses with PCS and MCS below/above their respective median values as dependent variables.

Results: 210 patients, age (median, IQR) 49.0 (40.0, 61.2) years were included. AS patients scored lower (p<0.001) compared to controls in all SF-36 domains and component summaries. Both sexes scored significantly lower in PCS compared to MCS. Multiple logistic regression analyses revealed that living without a partner (OR 2.38, 95% CI 1.00–5.67), long symptom duration (year in decade OR 1.66, 95% CI 1.16–2.37), higher BASFI (OR 1.98, 95% CI 1.46–2.70) and ASDAS≥2.1 (OR 3.32, 95% CI 1.45-7.62) were associated with worse PCS, while living without a partner (OR 3.04, 95% CI 1.34–6.91), fatigue (VAS global fatigue >median (OR 6.36, 95% CI 3.06–13.19) and ASDAS≥2.1 (OR 2.97, 95% CI 1.41–6.25) were associated with worse MCS.

Conclusions: AS patients had significantly lower HRQoL compared with controls. PCS was more affected than MCS in both sexes. Both disease related and demographic factors were associated with HRQoL, partly overlapping for PCS and MCS. Factors associated with HRQoL showed some differences between sexes. Modifying factors, such as ASDAS-CRP and fatigue, may improve HRQoL.

Objective: To describe treatment patterns in the Swedish early psoriatic arthritis cohort (SwePsA) of the mono-/oligo-arthritic (M/O) and polyarthritis (P) and identify early predictive factors for treatment with disease-modifying anti-rheumatic (DMARD), non-steroidal anti-inflammatory drugs (NSAID), and tumour necrosis factor inhibition (TNFi) after 5 years. Methods: Data for 198 M/O and P PsA were obtained within the programme for SwePsA. Multinomial and binary logistic regression analyses were used to assess the association between early predictive factors and treatment after 5 years adjusted for age at inclusion. The analysis of DMARD/NSAID was adjusted for medication at inclusion. Results: After inclusion visit, DMARD was prescribed in 30% of M/O and 56% of P PsA; mainly methotrexate. TNFi was not prescribed at inclusion, but 23 patients were treated at 5-year follow-up. The adjusted OR (95% CI) for treatment with both DMARD and NSAID after 5 years was 3.65 (1.34 - 9.89) (p=0.010) for Disease Activity Score 28 (DAS28) >3.2 and 2.90 (1.20-6.99) (p=0.038) for Disease Activity Index in Psoriatic Arthritis (DAPSA) >14 at inclusion. TNFi treatment was, after adjusting for age, associated with high erythrocyte sedimentation rate (p=0.0043), high C-reactive protein (p=0.013), DAPSA (p<0.001), not reaching minimal disease activity (p=0.001) high health assessment questionnaire (p=0.001), patient's overall assessment on the visual analogue scale (VAS) (p=0.009), high pain VAS (p=0.007), and high number of tender and swollen joints (p=0.031) at inclusion. Conclusion: Disease activity in early M/O and P PsA is to be considered in deciding the level of health care assessment and future pharmacological treatment. DAS28 >3.2 and DAPSA>14 early in the disease predict subsequent treatment with DMARD. For prediction of biological treatment, not reaching MDA at onset of disease, would be the composite index of choice.

BACKGROUND: There is a relationship between cardiovascular morbidity, inflammatory activity, and changes in the lipid profile in rheumatoid arthritis (RA), although the mechanisms are not fully elaborated. Recent know-ledge that white adipose tissue (WAT) is a producer of immunologically and metabolically active substances gives another perspective to study.

OBJECTIVE: To evaluate the relationship between interleukin-1 receptor antagonist (IL-1Ra) and variables associated with WAT and inflammation in RA.

METHODS: Anthropometric, inflammatory and metabolic variables were assessed in 23 women with RA and 23 matched controls. Spearman, partial correlation and factor analyses were performed.

RESULTS: Inflammatory markers were increased in patients. In both groups, IL-1Ra correlated with leptin independent of age and BMI. IL-1Ra also correlated with haptoglobin and apolipoprotein (Apo) B in patients and with soluble TNF receptor (sTNFR) 1 in controls. In factor analysis, three latent factors were identified among patients. The first loaded on IL-1Ra, leptin, BMI, ApoB and body fat content (BF%), the second loaded on IL1-Ra and sTNF-receptors and the third showed inverse loadings on ApoA-I together with loadings on ESR, haptoglobin, orosomucoid, BF% and BMI.

CONCLUSION: IL-1Ra was associated with markers of inflammation and with fat-related factors in RA patients, suggesting a dualistic relationship of IL-1Ra in RA. IL-1Ra correlated independently with leptin in both patients and controls, indicating a relationship between inflammation and leptin.

OBJECTIVE: To examine the incidence of, and outcome after, a stroke in patients with rheumatoid arthritis (RA) compared with the general population. METHODS: The northern Sweden MONICA register was used to compare the incidence of stroke in a cohort of RA patients with the general population. Forty RA patients who had also suffered a stroke were identified. For each patient with RA, three controls with a history of stroke but without RA were randomly collected from the same register, and matched for age and sex. RESULTS: The standardised incidence ratio (SIR) for stroke was 2.7 in RA patients compared with the general population (p<0.05). During the follow-up, RA patients had a higher overall case fatality (CF) following stroke compared with controls (hazard ratio (HR) =1.70, p<0.05). CONCLUSIONS: Both the incidence of a stroke, and the subsequent CF, were higher among RA patients compared with the general population. The results emphasize the necessity of optimising the prevention of stroke and follow-up care after a stroke in RA.

Objectives: To investigate the association between the onset of polymyalgia rheumatica (PMR) and prior or persistent infection with Chlamydia pneumoniae or cytomegalovirus (CMV), (both known to infect the vessel wall) enteroviruses (EV) or respiratory syncytial virus (RSV).

Methods: Serum samples were collected from 48 patients with newly-diagnosed PMR and from 22 controls of the same age. The presence of IgG, IgA and IgM antibodies to C. pneumoniae, IgG and IgM antibodies to CMV and EV, and complement fixing antibodies to RSV were analysed.

Results: Clinical symptoms of infection preceding PMR symptoms were associated with the presence of synovitis at the first visit. There were no significant differences in the seroprevalence rates of antibodies to C. pneumoniae, CMV, EV or RSV between PMR patients and controls. IgM antibodies to EV were found in two patients and IgM antibodies to CMV in another two patients.

Conclusion: Serological evidence of an association between newly-diagnosed PMR and prior or chronic infection with C. pneumoniae was not found. IgM antibodies to EV in two patients, consistent with ongoing or recent infection, suggest that EV could represent one of perhaps several microbes which are able to trigger PMR.

Objectives: Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aims of this study were to study the associations between subsets of T-cells, subclinical atherosclerosis assessed by intima-media thickness (IMT) and serological status for CMV in patients with RA.

Methods: Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were included in a prospective study of atherosclerosis. Controls matched for age and sex were also included (n=44). Ultrasound measurement of IMT in the common carotid artery was undertaken at inclusion (T0), after 1.5 years (T1.5) and after 11 years (T11). At T11, flow-cytometry analysis was undertaken to investigate subsets of T-cells. Serological analysis for CMV was undertaken from samples collected at T0.

Results: At T0, 66% of the patients and controls were CMV immunoglobulin G-positive. CMV-IgG positive patients had a significantly more rapid increase in IMT at T1.5, compared with controls and CMV-IgG negative patients. CMV-IgG positive patients had a significantly higher percentage of T-cells lacking CD28 (both CD4+CD28null and CD8+CD28null T-cells) than CMV-IgG negative patients. Increased levels of CD4+CD28null and CD8+CD28null T-cells were significantly associated with IMT at T11, adjusted for systolic blood pressure. CX3CR1 was expressed in CD4+ and CD8+ CD28null T-cells, but CX3CR1 per se was not associated with increased IMT.

Conclusions: Presence of CMV IgG-antibodies in patients with RA is associated with altered T-cell-populations and an increased burden of atherosclerosis. A possible protective effect of antiviral treatment in CMV-positive patients with new-onset RA should be considered.

OBJECTIVES:Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aim of this study was to examine the associations between subclinical atherosclerosis, assessed by intima-media thickness (IMT), and regulators of bone formation, markers of bone turnover and bone mineral density (BMD) in patients with RA.

METHODS:Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were consecutively included in a study of development of atherosclerosis. Ultrasound measurement of IMT of the common carotid artery was undertaken at inclusion (T0) and after 11 years (T11) (n=54). Bone turnover biomarkers were examined in samples collected at T0 and T11. BMD was assessed at T11.

RESULTS:In patients with RA, osteocalcin (OCN) and osteoprotegerin (OPG) measured at T11 were significantly associated with IMT at T11, adjusted for systolic blood pressure (SBP) and age. BMD at T11 and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and carboxy-terminal crosslinked C-terminal telopeptide (CTX) were not associated with IMT. OPG, OCN and sclerostin at T0 were significantly associated with IMT at T11, and OPG and OCN at T0 were associated with change in IMT from T0 to T11. The associations between IMT and bone biomarkers were stronger in patients with joint erosions at onset of RA, than in patients with non-erosive disease.

CONCLUSIONS:Atherosclerosis in patients with RA is associated with OPG and OCN, but not with BMD or markers reflecting ongoing bone turnover, indicating that atherosclerosis is not associated with bone turnover per se.

Objective Bombesin (BN) and the mammalian homologue gastrin-releasing peptide (GRP) are known trophic factors, neurotransmitters and paracrine hormones. BN/GRP has not previously been demonstrated in synovial fluid. In this study, the amounts of BN/GRP and substance P (SP) present in synovial fluid from the knee joints of patients with rheumatoid arthritis (RA) and of healthy, controls were measured.

Methods Synovial fluid from the knee joint was collected from patients with either longstanding RA (n = 32) or early arthritis (symptoms for < 12 months; n = 9) and from control subjects, i.e., individuals without known joint disease (n = 10). These samples were analyzed using radioimmunoassays.

Results Levels of BN/GRP-like peptide were below the assay detection limits in synovial fluid from controls. Detectable levels of immunoreactive BN/GRP were present in the majority of patients with either longstanding RA or early arthritis. The levels were significantly higher in the synovial fluid from patients classified as having early, arthritis compared with those with longstanding RA (p < 0.05). There was a strong correlation between BN/GRP levels and the number of leukocytes in the synovial fluid in the patients with early arthritis. The levels of SP-like peptide in the patients, whether with early arthritis or longstanding RA, were significantly elevated compared with controls. However there was no difference in the levels between these two patient groups.

Conclusions These observations show that BN/GRP-like peptide is present in the synovial fluid of joints affected by arthritis and that the pattern of BN/GRP increase differs from that of SP It appears as if the presence of BN/GRP is particularly related to the early processes of joint involvement. These observations are of interest because BN/GRP has well-known trophic and paracrine effects and chondrocytes have recently been shown to produce neuropeptides such as BN/GRP.

OBJECTIVE: To analyze candidate genes, related to cardiovascular disease (CVD) in general, and potentially involved in the inflammatory process, in RA patients from northern Sweden.

METHODS: Four hundred and sixty-seven individuals (345 females; 122 males) with RA (ACR criteria), having a mean age of 61.8 +/- 13.0 years and mean disease duration of 16.2 +/- 12.1 years, were consecutively recruited and followed-up for 3 years. The prevalence of CVD, [(ischemic heart disease (IHD), deep vein thromboses/pulmonary embolism (DVT/PE) and/or stroke/TIA] and hypertension was registered. Candidate genes encoding for Beta-fibrinogen (G-455A), Factor XIIIA (Val34Leu), plasminogen activator inhibitor type-1 (PAI-1 4G/5G), and tumor necrosis factor receptor (TNFR)II (M196R) were analysed. Controls (n = 672) were randomly selected according to age and gender from the Medical Biobank of Northern Sweden. Polymorphisms were genotyped using a TaqMan 9700HT and the 5'nuclease allelic discrimination assay.

RESULTS: The genotypes, carriers and alleles did not differ in distribution between patients and controls. Carriage of the TNFRII R variant was more frequent among patients with hypertension (p = 0.018). The genotype distribution of PAI-1 in patients with IHD differed significantly (p = 0.002) because carriage of 4G was more frequent (p = 0.024). Combined carriage of TNFRII 196R variant and Beta-fibrinogen-455A was a stronger predictor for hypertension than each genotype separately. The distribution of FXIIIA genotypes deviated significantly in RA patients with DVT/PE (p = 0.028) with an increased frequency of the Leu34 variant.

CONCLUSION: The unusual alleles of TNFRII, PAI-1 and FXIIIA were associated with CVD in RA patients. The combination of several of the rare types further increased the predictive values for CVD.