Complement activation prior to symptom onset in myeloperoxidase ANCA-associated vasculitis but not proteinase 3 ANCA associated vasculitis - A Swedish biobank study.

OBJECTIVE: Increased soluble levels of complement effectors have been demonstrated in active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but the timing of complement activation in the autoimmune inflammation remains elusive. This study investigated whether the complement system is activated before onset of symptoms in AAV. METHOD: The Swedish National Patient Register and Cause of Death register were linked to registers of five biobanks to identify individuals sampled before AAV symptom onset. Diagnosis of AAV and time-point for symptom onset were confirmed by reviewing medical records. We identified 64 presymptomatic individuals with serum samples > 1 month < 10 years from AAV symptom onset and 122 matched controls. Complement factors (C2, C5) and activation markers (C5a, C4b) were measured using Luminex technology. RESULTS: Presymptomatic individuals had higher levels of C5 up to 6.5 years before symptom onset, compared with controls [median (IQR) 80.7 (131.9) vs 46.6 (63.4) µg/mL, p = 0.05]. Levels of C5a increased significantly during the pre-dating time (p = 0.033) until symptom onset. The complement levels were significantly higher in presymptomatic myeloperoxidase (MPO)-ANCA+ individuals versus MPO-ANCA- and proteinase-3-ANCA+ individuals. C5 was significantly increased in cases with renal involvement at diagnosis versus controls (p = 0.022), whereas levels of both C5 and C5a were significantly increased in presymptomatic individuals diagnosed with microscopic polyangiitis after onset compared with controls (C5: p = 0.027; C5a: p = 0.027). CONCLUSION: Activation of the complement system is an early event in the pathogenesis of AAV and is mainly associated with MPO-ANCA+ AAV and with microscopic polyangiitis.

Association between inflammasome-related polymorphisms and psoriatic arthritis.

Objective: Psoriatic arthritis (PsA) is a heterogeneous inflammatory disease associated with psoriasis. Underlying genetic factors are considered important for disease expression and prognosis of PsA. Interleukin-1ß-regulating protein complexes called inflammasomes are associated with several inflammatory diseases, e.g. rheumatoid arthritis and psoriasis. The aim was to determine whether inflammasome-related genetic variation is associated with PsA susceptibility or different disease phenotypes.Method: DNA from 724 patients with PsA and 587 population-based controls from northern Sweden was analysed for single-nucleotide polymorphisms in NLRP3-Q750K (rs35829419), NLRP3 (rs10733113), CARD8-C10X (rs2043211), NLRP1 (rs8079034), and NLRP1 (rs878329).Results: Significant associations were found with the genotype AA (vs AT+TT) of rs2043211 for PsA patients compared with controls [odds ratio (OR), 95% confidence interval (CI) 1.32 (1.05-1.65), p = 0.016]; and between the C-allele of rs878329 and axial involvement of PsA [OR (95% CI) 1.37 (1.02-1.84), p = 0.035], the T-allele of rs8079034 with prescription of conventional synthetic disease-modifying anti-rheumatic drugs [OR (95% CI) 1.76 (1.23-2.53), p = 0.0020], the G-allele of rs10733113 and patients with a skin disease with early onset [OR (95% CI) 1.58 (1.13-2.21), p = 0.007], and the C-allele of rs35829419 and a destructive/deforming disease [OR (95% CI) 1.63 (1.04-2.55), p = 0.030].Conclusions: This study is the first to show an association with a genetic polymorphism in an inflammasome-related gene, CARD8-C10X (rs2043211), in patients with PsA. Associations between different phenotypes of PsA and different polymorphisms of the inflammasome genes were also found. Our results indicate the involvement of inflammasome genes in the pathogenesis and disease expression of PsA.

Anti-cyclic citrullinated peptide antibodies are associated with radiographic damage but not disease activity in early rheumatoid arthritis diagnosed in 2006-2011.

Objective: The discovery of anti-citrullinated protein antibodies (ACPAs) and the introduction of new therapeutic options have had profound impacts on early rheumatoid arthritis (RA) care. Since ACPA status, most widely assessed as reactivity to cyclic citrullinated peptides (CCPs), influences treatment decisions in early RA, we aimed to determine whether anti-CCP remains a predictor of disease activity and radiographic joint damage in more recent 'real-world' early RA. Method: Two observational early RA cohorts from Sweden enrolled patients in 1996-1999 (TIRA-1, n = 239) and 2006-2009 (TIRA-2, n = 444). Clinical and radiographic data and ongoing treatment were prospectively collected up to 3 years. Two other cohorts served as confirmation cohorts (TRAM-1, with enrolment 1996-2000, n = 249; and TRAM-2, 2006-2011, n = 528). Baseline anti-CCP status was related to disease activity, pharmacotherapy, and radiographic joint damage according to Larsen score. Results: In the TIRA-1 cohort, anti-CCP-positive patients had significantly higher 28-joint Disease Activity Score, swollen joint count, C-reactive protein level, and erythrocyte sedimentation rate during follow-up compared with anti-CCP-negative patients. In TIRA-2, no such differences were found, but baseline anti-CCP positivity was associated with higher 3 year Larsen score (5.4 vs 3.5, p = 0.039). In TRAM-2, anti-CCP also predicted radiographic damage (8.9 vs 6.7, p = 0.027), with no significant differences in disease activity. Conclusion: In the early RA cohorts recruiting patients in 2006-2011, baseline anti-CCP positivity was not associated with disease activity over time, but was associated with increased radiographic damage at follow-up. Hence, close radiographic monitoring is warranted in early anti-CCP-positive RA regardless of disease activity.

Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis.

Objective: Cardiovascular disease (CVD) is increased among patients with rheumatoid arthritis (RA). The underlying cause is not clear. In this prospective study, patients with early RA were investigated for associations between subclinical atherosclerosis and CVD risk factors as well as inflammation. Method: At diagnosis, RA patients were recruited into a prospective study. A subgroup was included (n = 55) for ultrasound measurements of intima-media thickness (IMT) at inclusion (T0), and after 5 years (T5) and 11 years (T11). Thirty-one age and gender-matched controls were also included for comparison. Results: IMT increased significantly between T0 and T11 among patients and controls (p < 0.0001). No statistically significant differences in IMT between patients and controls were detected at T11, T5, or T0 (p > 0.05 for all). In simple regression models, IMT at T11 was significantly associated with age (p < 0.0001), as well as systolic blood pressure at T0 (p < 0.01) and T11 (p < 0.01) among RA patients. Furthermore, the composite Systematic COronary Risk Evaluation (SCORE) measurements (p < 0.0001) and Reynolds risk score (p < 0.01) and the radiographic Larsen score (p < 0.05) at T0 were all significantly associated with IMT at T11. Results from conditional logistic regression analysis showed an increased progression rate between T0 and T11 in the RA group compared with controls (p < 0.05). Conclusion: We found increased atherosclerotic development among patients with RA compared with controls 11 years after diagnosis. The atherosclerotic burden was associated with disease severity at baseline.

Secretory antibodies to citrullinated peptides in plasma and saliva from rheumatoid arthritis patients and their unaffected first-degree relatives.

The aim of this study was to evaluate secretory antibodies to citrullinated proteins (ACPA) in plasma and immunoglobulin (Ig)A ACPA in saliva from patients with rheumatoid arthritis (RA) and their unaffected first-degree relatives (FDRs). Patients with RA (n = 194) and first-degree relatives unaffected by RA (n = 191) were recruited for analysis of secretory antibodies to second-generation cyclic citrullinated peptides (anti-CCP) in plasma. From a subpopulation (25 RA patients, 21 first-degree relatives and 11 controls), saliva samples were obtained for IgA anti-CCP analysis. The presence of secretory ACPA was compared between subject categories, and related to genetic and environmental risk factors. Secretory ACPA occurred in 37 (19%) plasma samples from patients with RA, but only in two (1%) of FDRs. IgA ACPA in saliva was found in three of 25 (12%) patients with RA, but not in any of the 21 FDRs (< 5%). No significant associations were seen between the presence of secretory ACPA and SE or smoking, either among RA patients or among FDRs. Despite occurring in 19% of RA plasma, secretory ACPA was rare in both saliva and plasma among FDRs, even among those positive for conventional ACPA of non-mucosal origin. Longitudinal studies are warranted to determine whether circulating secretory ACPA occurs before or in parallel with the development of clinical arthritis.

Individuals at risk of seropositive rheumatoid arthritis: the evolving story.

The aetiology of the autoimmune disease rheumatoid arthritis (RA) involves a complex interplay between genetic and environmental factors that initiate many years before the onset of clinical symptoms. These interactions likely include both protective and susceptibility factors which together determine the risk of developing RA. More than 100 susceptibility loci have been linked to RA. The strongest association is with HLA-DRB1 alleles encoding antigen presenting molecules containing a unique sequence in the peptide-binding grove called the 'shared epitope'. Female sex, infections during childhood, lifestyle habits (e.g. smoking and diet) and distinct microbial agents, amongst many others, are interacting risk factors thought to contribute to RA pathogenesis by dysregulating the immune system in individuals with genetic susceptibility. Interestingly, patients with RA develop autoantibodies many years before the clinical onset of disease, providing strong evidence that the lack of tolerance to arthritogenic antigens is amongst the earliest events in the initiation of seropositive RA. Here, we will discuss the clinical and mechanistic evidence surrounding the role of different environmental and genetic factors in the phases leading to the production of autoantibodies and the initiation of symptomatic RA. Understanding this complexity is critical in order to develop tools to identify drivers of disease initiation and propagation and to develop preventive therapeutics.

Concentrations of infliximab and anti-drug antibodies in relation to clinical response in patients with rheumatoid arthritis.

OBJECTIVE: The efficacy of anti-tumour necrosis factor-α (anti-TNF-α) treatment with infliximab (IFX) may be reduced by the development of anti-drug antibodies (ADAs). This study evaluated drug concentration and the presence of ADAs, relative to response, in rheumatoid arthritis (RA) patients treated with IFX. METHOD: Ninety-four RA patients were consecutively included and assessed for disease activity at baseline, and after 14, and 30 or 52 weeks. Serum IFX concentration and ADAs were analysed using in-house enzyme-linked immunosorbent assays. ADA analysis was based on binding to TNF-α-coated plates, with the lower detection limit set at mean + 2 sd of controls. RESULTS: At 14 and 52 weeks, 74.5% of the patients had moderate to good response. Good responders had significantly higher IFX concentrations than moderate and poor responders at 52 weeks (6.6 ± 1.4 µg/mL vs 3.6 ± 1.3 µg/mL and 2.6 ± 1.6 µg/mL, respectively). An IFX concentration ≥4.66 µg/mL at 14 weeks yielded a moderate to good response at 30/52 weeks, with 91.3% specificity and 39.3% sensitivity. Eleven patients dropped out owing to lack of efficacy and eight owing to side effects; three with IFX concentration ≤ 0.5 µg/mL were ADA positive. At an IFX concentration ≤ 0.5 µg/mL, 43.8% and 30.1% at 14 and 52 weeks, respectively, were ADA positive. None of the good responders had ADAs. CONCLUSION: One-quarter of patients had an IFX concentration ≤ 0.5 µg/mL but only 11.7% had ADAs. High IFX concentration was related to a good response, suggesting that the lack of response could be due to a lack of IFX, rather than to the presence of ADAs.

Association of valine and leucine at HLA-DRB1 position 11 with radiographic progression in rheumatoid arthritis, independent of the shared epitope alleles but not independent of anti-citrullinated protein antibodies.

OBJECTIVE: For decades it has been known that the HLA-DRB1 shared epitope (SE) alleles are associated with an increased risk of development and progression of rheumatoid arthritis (RA). Recently, the following variations in the peptide-binding grooves of HLA molecules that predispose to RA development have been identified: Val and Leu at HLA-DRB1 position 11, Asp at HLA-B position 9, and Phe at HLA-DPB1 position 9. This study was undertaken to investigate whether these variants are also associated with radiographic progression in RA, independent of SE and anti-citrullinated protein antibody (ACPA) status. METHODS: A total of 4,911 radiograph sets from 1,878 RA patients included in the Leiden Early Arthritis Clinic (The Netherlands), Umeå (Sweden), Hospital Clinico San Carlos-Rheumatoid Arthritis (Spain), and National Data Bank for Rheumatic Diseases (US) cohorts were studied. HLA was imputed using single-nucleotide polymorphism data from an Immunochip, and the amino acids listed above were tested in relation to radiographic progression per cohort using an additive model. Results from the 4 cohorts were combined in inverse-variance weighted meta-analyses using a fixed-effects model. Analyses were conditioned on SE and ACPA status. RESULTS: Val and Leu at HLA-DRB1 position 11 were associated with more radiographic progression (meta-analysis P = 5.11 × 10(-7)); this effect was independent of SE status (meta-analysis P = 0.022) but not independent of ACPA status. Phe at HLA-DPB1 position 9 was associated with more severe radiographic progression (meta-analysis P = 0.024), though not independent of SE status. Asp at HLA-B position 9 was not associated with radiographic progression. CONCLUSION: Val and Leu at HLA-DRB1 position 11 conferred a risk of a higher rate of radiographic progression independent of SE status but not independent of ACPA status. These findings support the relevance of these amino acids at position 11.

Diet and alcohol as risk factors for rheumatoid arthritis: a nested case-control study.

The aim of this study was to investigate whether alcohol and diet, assessed as both macronutrients and dietary patterns, increased the risk of development of rheumatoid arthritis (RA) through a nested case-control design in the Västerbotten Intervention Program (VIP) cohort. Individuals in the VIP who had developed RA after the dietary survey were identified from medical records at the department of rheumatology at the University Hospital, Umeå (n = 386), and matched to 1,886 controls from the same database. Diet was assessed as food groups, as macronutrients and as scores of dietary patterns, namely the carbohydrate-restricted diet score, the Mediterranean diet score and the healthy diet indicator score. When analysing the dietary patterns, consumption of food groups and different macronutrients, a significant association was found in the highest tertile of carbohydrate-restricted diet among the cases with a subsequent anti-CCP-positive disease 1.40 (1.02-1.92), as well as in the highest tertile of protein consumption among smokers (OR = 1.80, 95% CI 1.09-2.95). However, after additional adjustment for sodium intake, these associations were no longer statistically significant. No association was observed between alcohol consumption and the risk of RA. To summarize, there were no significant associations between diet, or alcohol consumption, and the risk of development of RA within this cohort. The lack of any significant associations of alcohol consumption may be explained by a low consumption in the studied population overall or alternatively by methodological issues raised recently.

Cytokines in relation to autoantibodies before onset of symptoms for systemic lupus erythematosus.

OBJECTIVES: A number of cytokines and chemokines were analysed and related to autoantibodies in blood samples pre-dating the onset of symptoms of systemic lupus erythematosus. METHODS: Thirty-five patients with systemic lupus erythematosus (American College of Rheumatology criteria) were identified as having donated blood samples, prior to symptom onset, to the Biobank of northern Sweden. Altogether, 140 age- and sex-matched controls were also identified. The concentrations of interferon-α, interleukin-4, interleukin-9, interleukin-10, interferon inducible protein-10 and monocyte chemotactic protein-1 were analysed using multiplex technology and related to autoantibodies (ANA, ENA, anti-dsDNA and anti-histone antibodies) analysed from the same blood sample. RESULTS: The interferon-γ inducible protein-10 levels were higher in the pre-symptomatic individuals than in controls (p < 0.05) and correlated with interferon-α (p < 0.01). The interferon-γ inducible protein-10 and interferon-α concentrations were significantly increased in individuals positive for autoantibodies: interferon-γ inducible protein-10 for ANA; anti-SSA/Ro and anti-Jo-1 antibodies; interferon-α with anti-SSB/La antibodies. The levels of interleukin-10, interferon-γ inducible protein-10 and monocyte chemotactic protein-1 increased significantly from the pre-symptomatic individuals to after onset of systemic lupus erythematosus. CONCLUSIONS: An increased concentration of interferon-γ inducible protein-10 pre-dated the onset of systemic lupus erythematosus and was related to autoantibodies before the onset of disease. The levels of interferon-γ inducible protein-10 and interferon-α were correlated. These findings support the proposal that the interferon system is important early in the pathogenesis of systemic lupus erythematosus and autoantibody formation.

Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility.

The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.

Changes in chemokines and their receptors in blood during treatment with the TNF inhibitor infliximab in patients with rheumatoid arthritis.

OBJECTIVES: Chemokines are involved in leucocyte recruitment into inflammatory sites. The release of certain chemokines is augmented by tumour necrosis factor (TNF). Infliximab, a monoclonal antibody that blocks the effects of TNF, is used for treatment of rheumatoid arthritis (RA). The effect of TNF blockage on chemokines is not fully understood. The aim of this study was to analyse the effects on chemokines and their receptors on peripheral mononuclear cells of anti-TNF treatment in RA patients. METHOD: Twelve patients with established RA who started treatment with infliximab and nine patients with early RA treated with other anti-rheumatic drugs were followed clinically for 30 weeks and chemokine levels in blood samples were analysed along with chemokine receptor expression on the surface of T cells and monocytes. Nine healthy subjects were included as a control group. RESULTS: The chemokine CXCL10/IP-10 was significantly higher in RA patients than in healthy controls (p = 0.012). Two weeks after infliximab infusion, CXCL10/IP-10, CCL2/MCP-1, and CCL4/MIP-1ß had decreased significantly (p = 0.005, 0.037, and 0.028, respectively), and after 30 weeks of treatment, soluble CD26 was significantly increased (p = 0.050). Several chemokine receptors on T cells were elevated in RA patients at inclusion. The expression of CCR2 and CXCR1 on T cells decreased significantly after infliximab treatment. CONCLUSIONS: The chemokines CXCL10/IP-10, CCL2/MCP-1, and CCL4/MIP-1ß, mainly targeting the T-helper (Th)1 immune response, decreased after treatment with anti-TNF, suggesting a more pronounced effect on Th1 activity than on Th2-mediated response. Several chemokine receptors on blood T cells were elevated in RA patients, suggesting that they may be involved in the recruitment of T lymphocytes from the blood to affected tissues.

Cardiovascular event in systemic lupus erythematosus in northern Sweden: incidence and predictors in a 7-year follow-up study.

INTRODUCTION: An increased rate of cardiovascular disease (CVD) has been suggested in patients with systemic lupus erythematosus (SLE). The risk for myocardial infarction (MI), coronary artery disease and stroke has been reported as particularly prevalent in younger females compared with the reference population. This study was performed to analyse the standard incidence ratio (SIR) of and predictors for cardiovascular events (CVEs) in patients with SLE from northern Sweden, with a fairly homogenous population. METHODS: In 2000 all prevalent patients with SLE (≥4 American College of Rheumatology [ACR] criteria; n = 277) from the four northern-most counties of Sweden were assessed with clinical and laboratory analyses. Seven years follow-up data concerning MI and stroke were extracted from the national registers of hospitalization and death in Sweden. The incidence ratio among the patients was compared with that for the general population from the same catchment area using data from the same register and Statistics Sweden. To identify time to event and CVE predictors, two matched controls for each patient were used and disease related variables as CVD predictors. RESULTS: The SIR for a CVE was 1.27 (95% CI 0.82-1.87) and for females separately aged 40-49 years was 8.00 (95% CI 1.65-23.38). The overall SIR for MI was 2.31 (95% CI 1.34-3.7), for females overall was 1.75 (95% CI 0.84-3.22) and for females aged between 40 and 49 years was 8.7 (95% CI 1.1-31.4). The time to an event was significantly shorter among SLE patients (p < 0.001) and was predicted by hypertension adjusted for smoking and disease. High SLEDAI and anti-cardiolipin IgG antibodies predicted an event in Cox proportional hazards regression models adjusted for age and previous MI. Diabetes, smoking ever and sex did not affect the prediction models. CONCLUSION: The risk of a CVE, or MI, was eight- or nine-fold greater among middle-aged female SLE patients. Time to event was significantly shorter and CVE was associated with SLE-related factors including hypertension and age.

Systemic lupus erythematosus and cardiac risk factors: medical record documentation and patient adherence.

This study explores patients' knowledge of cardiac risk factors (CRFs), analyses how information and advice about CRFs are documented in clinical practice, and assesses patient adherence to received instructions to decrease CRFs. Systemic lupus erythematosus (SLE) patients with ≥ 4 ACR criteria participated through completing a validated cardiovascular health questionnaire (CHQ). Kappa statistics were used to compare medical records with the self-reported CHQ (agreement) and to evaluate adherence. Two hundred and eleven (72%) of the known patients with SLE participated. The mean age of the patients was 55 years. More than 70% of the SLE patients considered hypertension, obesity, smoking and hypercholesterolaemia to be very important CRFs. The agreement between medical record documentation and patients' reports was moderate for hypertension, overweight and hypercholesterolaemia (kappa 0.42-0.60) but substantial for diabetes (kappa 0.66). Patients' self-reported adherence to advice they had received regarding medication was substantial to perfect (kappa 0.65-1.0). For lifestyle changes in patients with hypertension and overweight, adherence was only fair to moderate (kappa 0.13-0.47). Swedish SLE patients' awareness of traditional CRFs was good in this study. However, the agreement between patients' self-reports and medical record documentation of CRF profiles, and patients' adherence to medical advice to CRF profiles, could be improved.

Cytokine mRNA profile of alveolar T lymphocytes and macrophages in patients with systemic sclerosis suggests a local Tr1 response.

The development of an autoimmune disease like systemic sclerosis (SSc) is suspected to be driven by an activated T lymphocyte subset, expressing a cytokine profile specific to the disease. To further characterize the type of immune reaction in SSc, we searched for a broad panel of cytokine messenger ribonucleic acids (mRNAs) in T lymphocytes and monocytes/macrophages from paired samples of bronchoalveolar lavage fluid and peripheral blood in 18 patients and 16 age- and sex-matched controls. RNA from CD3(+) T lymphocytes and CD14(+) monocytes/macrophages was examined by means of the reverse transcriptase polymerase chain reaction. SSc alveolar T lymphocytes expressed a cytokine profile suggestive of a mixed Th1/Th2 reaction, showing an increased frequency of mRNA for interleukin (IL)-10, IL-6 and interferon (IFN)γ, while IL-1ß, IFNγ and tumour necrosis factor ß were expressed in blood T lymphocytes in a higher percentage of patients with SSc than controls. SSc alveolar T cells expressed IL-10 mRNA more often than peripheral T cells, a phenomenon not found in controls and which may point at local IL-10 activation/response in SSc lung. Transforming growth factor ß mRNA was present in all alveolar as well as peripheral blood T cell samples in patients and controls. The cytokine mRNA profile in SSc with interstitial lung disease (ILD) was similar to the profile found in SSc without ILD. Our findings point at a mixed Th1/Th2 reaction in SSc and may indicate regulatory T 1 cell activation/response in the lungs of patients with SSc.

Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006.

UNLABELLED: The risk of ischaemic heart disease (IHD), and in particular myocardial infarction (MI), is increased amongst patients with established rheumatoid arthritis (RA). Few studies have included contemporary patients with RA. We recently reported that the risk of IHD is not elevated before the onset of RA symptoms. However, when, in relation to RA diagnosis, the risk is increased is unknown. OBJECTIVE: To assess the risk of MI and other IHD events amongst patients diagnosed with RA during the last decade and within 18 months following RA symptom onset, compared to the general population, by time since RA diagnosis, year of RA diagnosis and by rheumatoid factor (RF) status. METHODS AND PATIENTS: A Swedish inception cohort of RA (n = 7469) diagnosed between 1995 and 2006 and a matched general population comparator cohort (n = 37,024), was identified and linked to national registers of morbidity and mortality from IHD. Relative risks (RRs) of MI and other IHD events were estimated using Cox regression. RESULTS: During follow-up, 233 patients with RA and 701 controls developed a first MI, corresponding to an overall RR of MI of 1.6 (95% confidence interval 1.4, 1.9). Increased risks of MI were already detected within 1-4 years following RA diagnosis, as well as in patients diagnosed with RA during the last 5 years, in RF-negative patients and for transmural as well as nontransmural MIs. CONCLUSIONS: MI risk increases rapidly following RA diagnosis, suggesting the importance of additional mechanisms other than atherosclerosis. The elevated short-term risk is present amongst patients diagnosed in recent years, underscoring the importance of MI prevention from the time of RA diagnosis.

Influence of female hormonal factors, in relation to autoantibodies and genetic markers, on the development of rheumatoid arthritis in northern Sweden: a case-control study.

OBJECTIVES: To study the influence of female hormonal factors on the development of rheumatoid arthritis (RA) in relation to the human leucocyte antigen (HLA)-DRB1 shared epitope (SE), the protein tyrosine phosphatase (PTPN22) 1858T variant, anti-citrullinated protein antibodies (ACPAs), and immunoglobulin (Ig)M-rheumatoid factor (IgM-RF). METHODS: A case-control study (1:4) was nested within the Medical Biobank of northern Sweden. Females who had subsequently developed RA (n = 70), median of 2.7 years before the onset of symptoms, and matched controls (n = 280) were identified from among the blood donors. A questionnaire concerning previous exposures until disease onset, including hormonal and reproductive factors, and smoking habits was distributed. RESULTS: Breastfeeding was significantly associated with the development of RA [odds ratio (OR) 4.8, 95% confidence interval (CI) 1.43-15.8]. Increasing time of breastfeeding increased the risk of RA (OR 5.7, 95% CI 1.83-17.95) for breastfeeding ≥ 17 months. In a multiple logistic regression analysis, increasing time of breastfeeding (OR 9.5, 95% CI 2.14-42.43 for ≥ 17 months), seropositivity for ACPAs (OR 19.5, 95% CI 4.47-84.81), and carriage of the PTPN22 1858T variant (OR 3.2, 95% CI 1.36-7.54) remained significant predictors of RA. Users of oral contraceptives (OC) for ≥ 7 years had a decreased risk for development of RA (OR 0.37, 95% CI 0.15-0.93). CONCLUSIONS: A longer duration of breastfeeding increased the risk of developing RA, especially among individuals seropositive for ACPA or IgM-RF or carrying the PTPN22 1858T variant. Use of OC for ≥ 7 years was associated with a decreased risk.

Atherothrombotic events in rheumatoid arthritis are predicted by homocysteine - a six-year follow-up 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.

Interleukin-6 and soluble interleukin-2 receptor alpha-markers of inflammation in patients with psoriatic arthritis?

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.