Proprotein convertase enzyme FURIN is upregulated in primary Sjögren's syndrome.

OBJECTIVES: The proprotein convertase enzyme FURIN is a critical regulator of the anti-inflammatory TGFß-1 cytokine and peripheral immune tolerance. In T cells, FURIN is co-regulated with IFN-γ and thus highly expressed in T helper 1 type cells. Previous studies have demonstrated that FURIN is upregulated in inflammatory conditions, including atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus. Here, we evaluated the levels of FURIN in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with primary Sjögren's syndrome (pSS) and in healthy controls. METHODS: FURIN plasma levels were determined by ELISA, and the mRNA expression in PBMCs was quantitated using qPCR. FURIN levels in the plasma were correlated with the clinical and demographic characteristics of the patients. RESULTS: FURIN was found to be significantly upregulated at both the protein and mRNA level in pSS patients compared to healthy controls. In pSS patients, high FURIN protein levels were significantly associated with elevated IFN-γ levels in the plasma as well as a longer duration of sicca symptoms in the eyes. pSS patients with high FURIN levels in their plasma showed a trend towards lower levels of serum beta-2 microglobulin, ESR and a lower systemic disease activity index ESSDAI. CONCLUSIONS: The proprotein convertase FURIN is significantly upregulated in pSS. Elevated FURIN levels associate with high levels of the Th1 type cytokine IFN-γ and long duration of dry eye symptoms. Patients with high FURIN levels show signs of lower disease activity suggesting that FURIN might have a protective role in pSS.

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome.

Limited data are available regarding the intracellular responses to different cytokines in primary Sjögren's syndrome (pSS). We studied the signal transducer and activator of transcription (STAT) activation profile in response to cytokine stimulations in peripheral blood mononuclear cells (PBMCs) from pSS patients by multicolor flow cytometry. The expression of the suppressors of cytokine signaling (SOCS), and interferon (IFN)-γ target genes in PBMCs was studied using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The induction of STAT1 phosphorylation in response to stimulation with IFN-α, IFN-γ or interleukin (IL)-6 was significantly increased in B cells and monocytes from pSS patients. Accordingly, the STAT1-mediated gene responses were significantly enhanced in PBMCs from pSS patients. Finally, the expression of SOCS1 and SOCS3 mRNA was increased in pSS patients. The results indicate increased sensitivity of immune cells from pSS patients to STAT1-activating signals, and may partly explain the IFN signature observed in pSS.

Effectiveness and Drug Survival of TNF Inhibitors in the Treatment of Ankylosing Spondylitis: A Prospective Cohort Study.

OBJECTIVE: The aim of this research was to describe the effectiveness and drug survival of tumor necrosis factor (TNF) inhibitors in the treatment of ankylosing spondylitis (AS) and to analyze the effect of concomitant treatment with conventional disease-modifying antirheumatic drugs. METHODS: Patients with AS identified from the National Register for Biologic Treatment in Finland starting their first TNF inhibitor treatment between July 2004 and December 2011 were included. Treatment response was measured as an improvement of 50% (or 20 mm) after 6 months of treatment onset compared to the baseline Bath AS Disease Activity Index (BASDAI) score. Treatment response and 2-year drug survival were modeled with logistic regression and time-dependent Cox proportional hazard models, respectively. RESULTS: The study comprised 543 patients, of whom 123 also commenced a second TNF inhibitor during the followup. Treatment was discontinued within 24 months by 25% and 28% of the users of the first and the second TNF inhibitors, respectively. BASDAI response at 6 months was achieved by 52% and 25% of the users of the first and the second TNF inhibitors, respectively. Etanercept (ETN; HR 0.42, 95% CI 0.29-0.62) and adalimumab (ADA; HR 0.48, 95% CI 0.30-0.77) were associated with better drug survival in comparison to infliximab (IFX). Also, concurrent use of sulfasalazine (SSZ; HR 0.70, 95% CI 0.49-0.99) decreased the hazard for treatment discontinuation. CONCLUSION: TNF inhibitors are equipotent in the treatment of AS; however, ETN and ADA were found superior to IFX in drug survival. The use of SSZ improves treatment continuation.

ESSPRI and other patient-reported indices in patients with primary Sjogren's syndrome during 100 consecutive outpatient visits at one rheumatological clinic.

OBJECTIVE: A European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and a patient-reported index (ESSPRI) have recently been developed and validated. In our previous study the ESSDAI correlated significantly with serum ß2 microglobulin concentration. We now aim to establish whether the ESSPRI is also associated with serum ß2 microglobulin or with other patient-reported indices. METHODS: The data on 100 consecutive visits of patients with primary SS (pSS) were reviewed from the patient charts. Patients who had filled out the ESSPRI questionnaire and fulfilled at least four of the revised American-European consensus group criteria for pSS were included. Data were gathered on the ESSPRI (0-10 cm) and on the patient's global health assessment [visual analogue scale (VAS) 0-10 cm] (PGH-VAS), pain-VAS (0-10 cm) and HAQ (range 0-3). RESULTS: The ESSPRI correlated significantly with the PGH-VAS (r = 0.753, P < 0.0001), pain-VAS (r = 0.656, P < 0.0001) and HAQ (r = 0.542, P < 0.0001) (Spearman's correlation). It also correlated weakly with serum ß2 microglobulin (r = 0.214, P = 0.043) and ESR levels (r = 0.235, P = 0.019). CONCLUSION: The ESSPRI correlated significantly with other patient-reported indices, serum ß2 microglobulin and ESR in patients with pSS. Our results support the view that the ESSPRI is a useful tool in the follow-up of patients with pSS.

Novel carbonic anhydrase autoantibodies and renal manifestations in patients with primary Sjogren's syndrome.

OBJECTIVE: Anti-carbonic anhydrase II (anti-CA II) antibodies have been related to renal manifestations of primary SS (pSS), and animal studies have even suggested a pathogenic role for them. However, not all pSS patients with renal tubular acidosis (RTA) present with anti-CA II antibodies. Recently, several novel CA isoenzymes have been recognized and we aimed to investigate whether antibodies to these are associated with renal manifestations of pSS. METHODS: We examined anti-CA II antibodies as well as anti-CA I, VI, VII and XIII antibodies by ELISA tests in 74 pSS patients on whom detailed nephrological examinations had been performed and, as controls, in 56 subjects with sicca symptoms, but no pSS. RESULTS: The levels of anti-CA I, II, VI and VII antibodies were significantly higher in patients with pSS compared with subjects with sicca symptoms but no pSS. None of the anti-CA antibodies was associated with the presence of complete or incomplete RTA or proteinuria or urinary α1m excretion in patients with pSS. However, levels of anti-CA II, VI and XIII antibodies correlated significantly with urinary pH, and inversely with serum sodium concentrations. The degree of 24-h urinary protein excretion correlated weakly with levels of anti-CA VII antibodies. CONCLUSION: Not only antibodies to CA II, but also anti-CA VI and XIII antibodies seem to be associated with renal acidification capacity in patients with pSS.

High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients.

Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan (trp) catabolism, may play a critical role in various inflammatory disorders. Recent studies on trauma patients have suggested that the degradation of trp is associated with the development of sepsis. The role of IDO activity in bacteremic patients is unclear. We studied IDO activity in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococcae, or Eschericia coli. The serum concentrations of trp and its metabolite kynurenine (kyn) were measured by reverse-phase high-performance liquid chromatography 1 to 4 days after the positive blood culture and on recovery. The kyn-to-trp ratio (kyn/trp), reflecting the activity of the IDO enzyme, was calculated. The maximum value in the ratio for every patient during 1 to 4 days after positive blood culture was used in analysis. The maximum kyn/trp ratio was significantly higher in nonsurvivors versus those who survived (193.7 vs. 82.4 micromol/mmol; P = 0.001). The AUC(ROC) of maximal kyn/trp in the prediction of case fatality was 0.75 (95% confidence interval, 0.64-0.87), and the kyn/trp ratio at a cutoff level of 120 micromol/mmol showed 83% sensitivity and 69% specificity for fatal disease. A kyn/trp ratio greater than 120 micromol/mmol was associated with increased risk of death versus low (

Serum amyloid A and C-reactive protein concentrations are differently associated with markers of autoimmunity in patients with primary Sjögren's syndrome.

OBJECTIVE: Primary Sjögren's syndrome (pSS) is an autoimmune disease in which the concentration of the acute-phase protein serum C-reactive protein (CRP) is low. We investigated whether levels of another acute-phase protein, serum amyloid A (SAA), are increased in patients with pSS and whether the immunological markers in patients with pSS are associated with variation in SAA levels. METHODS: Serum SAA concentrations were measured by ELISA in 74 patients with pSS and in 56 control subjects with sicca symptoms. RESULTS: Median SAA levels did not differ significantly between patients with pSS and subjects with sicca symptoms. In patients with pSS SAA concentrations correlated significantly with age, leukocyte count, CRP, interleukin 6, and C4. Unlike CRP, there was a significant inverse correlation between SAA and serum IgG levels and anti-SSA antibody titers, as well as a trend towards an inverse correlation between SAA and antinuclear antibody and rheumatoid factor titers. CONCLUSION: Our data imply that high SAA production could constitute a protective element in pSS: high SAA levels inhibit in particular various signs of B cell hyperreactivity, i.e., IgG and autoantibody production.

Autoimmunity and atherosclerosis: the presence of antinuclear antibodies is associated with decreased carotid elasticity in young women. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: There is ample evidence demonstrating that accelerated atherosclerosis prevails in autoimmune rheumatic diseases, particularly in SLE, and that the risk is due not only to traditional cardiovascular risk factors but also to the disease itself. ANAs are a hallmark of SLE and are known even to antedate the development of SLE. Our aim was to investigate whether positive ANAs in young adults are associated with risk factors for atherosclerosis or subclinical markers of atherosclerosis. METHODS: ANAs were examined by IIF using HEp-2 cells as substrate in 2278 participants in the Cardiovascular Risk in Young Finns Study for whom detailed data on cardiovascular risk factors and markers of subclinical atherosclerosis (including brachial flow-mediated dilatation, carotid compliance and carotid intima-media thickness) were available. RESULTS: In multivariate analyses, adjusted for age, BMI, serum concentrations of CRP, triglycerides, high-density lipoprotein and low-density lipoprotein cholesterol, blood pressure and smoking habits, ANA positivity (titre > 160) was inversely associated (beta = -0.145; P = 0.034) with carotid compliance in women. CONCLUSIONS: Our results indicate that ANA positivity is associated with decreased carotid elasticity in women, suggesting that mechanisms resulting in ANA production may be involved in the development of early atherosclerosis.

The association between burnout and physical illness in the general population--results from the Finnish Health 2000 Study.

OBJECTIVE: The association between burnout and physical diseases has been studied very little. The purpose of this study was to examine the relationship between burnout and physical illness in a representative nationwide population health study. METHODS: As a part of the "Health 2000 Study" in Finland, 3368 employees aged 30-64 years were studied. Burnout was assessed with the Maslach Burnout Inventory-General Survey. Physical diseases were diagnosed in a comprehensive health examination by research physicians. RESULTS: Physical illness was more common among subjects with burnout than others (64% vs. 54%, P<.0001), and the prevalence of diseases increased with the severity of burnout (P<.0001). Burnout was an important correlate of cardiovascular diseases among men (OR=1.35; 95% CI, 1.13-1.61) and musculoskeletal disorders among women (OR=1.22, 95% CI, 1.07-1.38) when adjusted for age, marital status, education, socioeconomic status, physical strenuousness of work, smoking, physical activity, alcohol consumption, body mass index, and depressive symptoms. The prevalence of musculoskeletal disorders and cardiovascular diseases increased with the severity of all three dimensions of burnout, that is, exhaustion (P<.0001 and P<.001, respectively), cynicism (P=.0001 and P<.001, respectively), and lack of professional efficacy (P<.01 and P<.0001, respectively). CONCLUSIONS: Burnout is associated with musculoskeletal diseases among women and with cardiovascular diseases among men. These associations are not explained by sociodemographic factors, health behavior, or depression. Physical illnesses are associated with all three dimensions of burnout and not only with the exhaustion dimension. In the future, the causal relationships between burnout and physical diseases need to be investigated in prospective studies.

IgA levels are predictors of mortality in Finnish nonagenarians.

It has been demonstrated that in obviously healthy, very old people increased levels of inflammatory markers as well as some defects in T lymphocyte populations are strong predictors of mortality. Very little is known about the role of possible functional defects in antibody formation. To examine this, we now measured IgM, IgG and IgA concentrations in a cohort of 285 nonagenarians (67 males, 218 females). IgG and IgA levels were significantly higher than those of healthy middle-aged controls. The analyzed serum samples were taken at the age of 90-91 years. After 4 years, 20 males and 94 females had survived. To analyze the role in predicting mortality, the immunoglobulin data (as well as the measured CRP and IL-6 concentrations) were stratified according to this survival data. IgA levels (and CRP and IL-6 levels) were clearly higher in the nonsurvivors than in the survivors. These data imply that elevated serum IgA level, i.e. indicator of intestinal inflammation and/or defect in mucosal defence, is a strong mortality predicting factor.

Immunoglobulin KM and GM gene polymorphisms modify the clinical presentation of primary Sjögren's syndrome.

OBJECTIVE: To investigate whether polymorphism of immunoglobulin (Ig) genes affects susceptibility to or severity of primary Sjogren's syndrome (pSS). METHODS: Ig gene kappa (KM) and gamma (GM) polymorphisms were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) based method in 65 Finnish Caucasian patients with pSS and in 66 healthy controls matched for sex, ethnic origin, and area of residence. Clinical and immunological data on the pSS patients were analyzed in relation to Ig genotypes. RESULTS: The genotype frequencies of Ig KM and GM genes did not differ between pSS patients and controls. Anti-SSB antibodies were encountered significantly more frequently in pSS patients carrying the KM1 allele than in those without (100% vs 48%, p = 0.016). The pSS patients with the KM1 allele had several signs of immunologically active disease: they had significantly higher erythrocyte sedimentation rate, serum IgA, serum beta2-microglobulin (beta2-m), and plasma IgG1 concentrations than patients without this allele. The pSS patients carrying the GM z allele had a milder form of pSS than those without this determinant. They had less severe labial salivary gland histological findings (grade 3-4 in 60% vs 93%, p = 0.004) and lower plasma IgG3 and serum beta2-m concentrations than those without GM z allele. CONCLUSIONS: Ig KM and GM genes do not contribute to susceptibility to pSS. The Ig KM1 allele is associated with several markers of immunologically active disease, whereas the Ig GM z allele is associated with milder pSS.