Endothelial dysfunction in patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is associated with accelerated atherosclerosis and enhanced cardiovascular morbidity and mortality compared to the general population. The mechanisms and mediators of this phenomenon have not been fully explained, but an expanding body of evidence demonstrates that increased cardiovascular risk in AS is heralded by endothelial dysfunction. We performed a literature review using the PubMed database from the year 2006 up to 2018. In this article we review the epidemiology, current evidence for impaired endothelial function, potential mechanisms and markers controlling this dysfunction, and finally we summarize the data regarding the efficacy of pharmacotherapy in reducing endothelial dysfunction in patients suffering from AS.

Vitamin D serum concentration is not related to the activity of spondyloarthritis - preliminary study.

OBJECTIVE: Vitamin D plays an important role in mineral turnover and bone remodeling and there are increasing data about its immunomodulatory potential in different rheumatologic disorders. Deficiency of vitamin D is frequent in patients with spondyloarthritis (SpA) and some data suggest its association with increased disease activity and structural damage. However, its exact role in the pathogenesis of SpA and its association with disease activity are still a matter of debate. MATERIAL AND METHODS: A cross-sectional study of patients diagnosed with axial spondyloarthritis (axSpA) and peripheral spondyloarthritis (perSpA) according to Assessment of Spondyloarthritis International Society classification criteria was performed. The correlation between concentration of 25-hydroxyvitamin D - 25(OH)D - and disease activity scores (Bath Ankylosing Spondylitis Disease Activity Index - BASDAI, Ankylosing Spondylitis Disease Activity Score - ASDAS), inflammatory markers (C-reactive protein - CRP, erythrocyte sedimentation rate - ESR) and clinical symptoms (arthritis, enthesitis, dactylitis) was performed. RESULTS: We included 40 patients with axSpA and 23 patients with perSpA. The mean concentration of 25(OH)D was 24.9 ng/ml (SD 12.49). Forty-seven (74.6%) patients had 25(OH)D below the recommended threshold (< 30 ng/ml). We found no statistically significant negative correlation between the level of 25(OH)D and disease activity of axSpA and perSpA in terms of clinical symptoms (arthritis, enthesitis, dactylitis), inflammatory markers (ESR, CRP) and disease activity scores (BASDAI, ASDAS). These results did not change after adjustment for supplementation of vitamin D and seasonal variation. CONCLUSIONS: Our data show no correlation between the concentration of 25(OH)D in the serum and disease activity in two subgroups of SpA. However, this does not exclude the potential role of vitamin D in pathogenesis of SpA. Further studies are required to evaluate the optimal range of 25(OH)D serum concentration in axSpA and perSpA patients with its possible immunomodulatory potential and influence on disease activity.

Results from Polish Spondyloarthritis Initiative registry (PolSPI) - methodology and data from - the first year of observation.

OBJECTIVES: Report on one-year results from the Polish Spondyloarthritis Initiative registry (PolSPI), containing the cross-sectional analysis of clinical and imaging data as well as database methodology. MATERIAL AND METHODS: The PolSPI registry includes patients with axial (axSpA) and peripheral (perSpA) spondyloarthritis according to ASAS classification criteria, and/or patients with ankylosing spondylitis according to modified New York criteria, psoriatic arthritis according to CASPAR criteria, arthropathy in inflammatory bowel disease, reactive arthritis, juvenile spondyloarthritis or undifferentiated spondyloarthritis. Epidemiologic data and history of signs, symptoms and treatment of spondyloarthritis are collected and assessment of disease activity is performed. Radiographic images of sacroiliac joint, cervical and lumbar spine, and results of bone densitometry are collected. Every 6 months blood samples for inflammatory markers, and for long-term storage are taken. RESULTS: During a one-year period from September 2015 to August 2016, 63 patients were registered on an electronic database; 44 (69.8%) of patients were classified as axial spondyloarthritis (axSpA) and 19 (30.2%) as peripheral spondyloarthritis (perSpA) according to ASAS criteria. Statistically significant differences between axSpA and perSpA were discovered in the percentage of HLA-B27 antigen occurrence (92.6% and 50%, respectively), BASDAI (2.8% and 4.1%, respectively), DAS 28 (2.66% and 4.03%, respectively), percentage of peripheral arthritis (20% and 88.8%, respectively), enthesitis (26.7% and 70.6%, respectively), dactylitis (6.7% and 88.9%, respectively), as well as extra-articular symptoms: acute anterior uveitis (26.7% and 5.6%, respectively) and psoriasis (6.9% and 55.6%, respectively). Patients with axSpA had significantly higher mean grade of sacroiliac involvement according to New York criteria, higher mSASSS score, and lower T-score in femoral neck in bone densitometry. CONCLUSIONS: At the early stage of the disease patients with axSpA compared to those with perSpA, have more advanced structural damage of sacroiliac joints and spine, and lower bone mineral density in the femoral neck. In the upcoming years the PolSPI registry will prospectively follow-up patients with SpA, recording response to treatment and carrying out research on interaction of inflammation and bone remodelling.

Differential associations of inflammatory and endothelial biomarkers with disease activity in rheumatoid arthritis of short duration.

OBJECTIVES: To estimate endothelial dysfunction in patients with rheumatoid arthritis (RA) of short duration in relation to disease activity based on the assessment of 28 joints (DAS28). METHODS: We studied 29 patients (22 women, mean age 41 (SD, 9) years) with RA of short duration and 29 healthy controls. The RA subjects were divided into those with low (DAS28: 2.6-5.1, n = 18) or high (DAS28 > 5.1, n = 11) disease activity. Exclusion criteria included clinically overt atherosclerosis and other coexistent diseases. Biochemical markers of inflammatory activation and endothelial dysfunction were measured. RESULTS: There were no significant intergroup differences in the majority of classical cardiovascular risk factors. High-sensitivity C-reactive protein, tumor necrosis factor- α , and interleukin-6 were increased in RA subjects. Compared to the controls, levels of soluble vascular cell adhesion molecule-1, von Willebrand factor, and pentraxin-3 were significantly elevated in RA subjects with low disease activity, exhibiting no further significant rises in those with high disease activity. Asymmetric dimethyl-L-arginine, soluble E-selectin, monocyte chemotactic protein-1, and osteoprotegerin were increased only in RA patients with high disease activity. CONCLUSIONS: Our findings might suggest a dissociation of pathways governing generalized and joint-specific inflammatory reactions from those involved in endothelial activation and inflammation within the vascular wall.

Alterations in skin microvascular function in patients with rheumatoid arthritis and ankylosing spondylitis.

OBJECTIVE: To evaluate the relationship between systemic inflammation and skin microcirculation in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS: We assessed skin microcirculation flux (laser Doppler flowmetry), classical cardiovascular risk factors, inflammatory markers and disease activity (Disease Activity Score 28, Bath Ankylosing Spondylitis Disease Activity Index) in 75 patients with arthritis with a median disease duration of 4 years, and in 26 healthy subjects. RESULTS: In patients with arthritis inflammatory markers (C-reactive protein, interleukin 6, fibrinogen) were increased, peak flux velocity after the occlusion at the temperature of 36.6°C and maximal heat flux velocity after the heating were significantly lower. These findings were accompanied by the slower increase in the flux rate during local heating. There were positive correlations between inflammatory markers and microcirculation parameters in patients with RA and AS, but only for RA patients between peak flux velocity and disease activity. There were no significant intergroup differences when the classical cardiovascular risk factors were compared except for the lower HDL cholesterol in arthritis patients. CONCLUSIONS: Patients with chronic systemic inflammatory arthritis presented altered microvascular function and reduced vasodilator capacity of the forearm skin microcirculation.

Oxidative modification of type II collagen differentially affects its arthritogenic and tolerogenic capacity in experimental arthritis.

INTRODUCTION: Oxidative modification of proteins affects their biological properties. Previously we have shown that hypochlorite (HOCl), the product of activated neutrophils, enhances protein immunogenecity. Collagen type II, a primary component of cartilage, is commonly used in the induction of arthritis in animals (CIA). The aim of this study was to examine whether HOCl may affect immunogenic, tolerogenic, and arthritogenic properties of collagen. MATERIALS AND METHODS: DBA/J mice were injected with either native (CNAT) or chlorinated collagen (CHOCl) to induce arthritis. The effect of chlorination on collagen properties was measured by evaluation of incidence and severity of CIA. Moreover, the concentration of serum anti-collagen IgG antibodies and myeloperoxidase (MPO) activity in inflamed joints was determined. RESULTS: Mice immunized with CNAT in adjuvant developed arthritis (CIA) with an incidence of 69%. CNAT also exerted tolerogenic properties when injected intravenously either before or shortly after primary immunization, resulting in decreased incidence and severity of CIA, reduced MPO activity in inflamed joints, and lowered serum levels of anti-CNAT IgG anti-bodies. Chlorination of collagen significantly diminished its ability to induce CIA and to trigger generation of anti-CNAT IgG antibodies. Interestingly, chlorination did not affect tolerogenic properties of collagen administered prior to primary immunization with CNAT. CONCLUSIONS: These results suggest that chlorination of collagen may selectively affect functional epitopes of collagen. It is likely that in inflamed joints, neutrophil derived HOCl, in some circumstances, will destroy arthritogenic and immunogenic B cell epitopes, while regulatory T cell epitopes will be preserved.

Blood monocyte subsets and selected cardiovascular risk markers in rheumatoid arthritis of short duration in relation to disease activity.

OBJECTIVES: To evaluate blood monocyte subsets and functional monocyte properties in patients with rheumatoid arthritis (RA) of short duration in the context of cardiovascular (CV) risk and disease activity. METHODS: We studied conventional markers of CV risk, intima media thickness (IMT), and blood monocyte subsets in 27 patients aged 41 ± 10 years with RA of short duration (median 12 months) and 22 healthy controls. The RA subjects were divided into low (DAS28: 2.6-5.1) and high (DAS28 > 5.1) disease activity. RESULTS: RA patients exhibited increased levels of intermediate (CD14(++)CD16(+)) monocytes with decreased CD45RA expression compared to controls, increased counts of classical (CD14(++)CD16(-)) monocytes, and decreased percentages of nonclassical (CD14(+)CD16(++)) monocytes. Patients with high disease activity had lower HLA DR expression on classical monocytes compared to low disease activity patients. There were no differences in monocyte subsets between subjects with DAS > 5.1 and DAS ≤ 5.1. There were no significant intergroup differences in IMT and the majority of classical CV risk factors. CONCLUSIONS: Patients with RA of short duration show alteration in peripheral blood monocyte subsets despite the fact that there is no evidence of subclinical atherosclerosis. Disease activity assessed with DAS28 was associated with impaired functional properties but not with a shift in monocyte subpopulations.

Plasma asymmetric dimethylarginine in active rheumatoid arthritis: links with oxidative stress and inflammation.

INTRODUCTION:  Endothelial dysfunction and accumulation of asymmetric dimethylarginine (ADMA) have been identified as independent predictors of future cardiovascular events in patients with coronary artery disease. OBJECTIVES:  The aim of the study was to investigate the factors that determine increased accumulation of ADMA, an endogenous inhibitor of nitric oxide synthesis, in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS:  We studied 46 consecutive patients with RA (39 women, 7 men; mean age, 57 years [range, 23-75 years]) with active disease (mean Disease Activity Score 28 [DAS28], 5.2), without clinically overt cardiovascular disease and 50 controls matched for age, sex, hypertension, blood cholesterol, and glucose. We assessed the plasma levels of ADMA, symmetric dimethylarginine (SDMA), L­arginine, and the marker of oxidative stress, 8­iso­prostaglandin F2α (8­iso­PGF2α).  RESULTS:  ADMA and SDMA levels were significantly higher in the RA group than in controls (0.58 ±0.081 vs. 0.46 ±0.045 µmol/l, P <0.0001; 0.45 ±0.07 vs. 0.36 ±0.046 µmol/l, P <0.0001; respectively). ADMA levels in the RA group correlated positively with fibrinogen (r = 0.70, P <0.00001), C­reactive protein (CRP; r = 0.88, P <0.00001), DAS28 (r = 0.44, P = 0.002) and Health Assessment Questionnaire scores (r = 0.39, P = 0.008), but not with age, renal function, or the medications used. 8­iso­PGF2α correlated positively with ADMA (r = 0.82), SDMA (r = 0.72), CRP (r = 0.76), fibrinogen (r = 0.57) (all, P <0.0001) and DAS28 (r = 0.44, P = 0.003). Regression analysis models showed that CRP was the only independent predictor of 8­iso­PGF2α and ADMA levels in RA. CONCLUSIONS:  Our study is the first to show positive associations between plasma ADMA levels and the production of 8­isoprostanes and CRP in RA.

Unfavorably altered fibrin clot properties in patients with active rheumatoid arthritis.

OBJECTIVE: Altered fibrin clot properties have been reported in cardiovascular diseases (CVD) and inflammatory states. Given increased prevalence of CVD in patients with rheumatoid arthritis (RA), we investigated whether fibrin characteristics are also altered in RA patients. PATIENTS AND METHODS: We studied 46 consecutive RA patients versus 50 controls matched for age and gender. Ex vivo plasma clot permeability, turbidity, tissue-type plasminogen activator (tPA)-induced fibrinolysis, and scanning electron microscopy (SEM) images of clots were evaluated. RESULTS: Patients with RA had lower clot permeability, faster clot formation, higher maximum clot absorbency indicating thicker fibrin fibers, maximum clot mass and prolonged fibrinolysis time than controls. Maximum rates of clot lysis were similar in both groups. SEM images showed formation of dense clots with many projections on fibrin fibers. Clot permeability inversely correlated with fibrinogen, tPA, plasminogen activator inhibitor-1 (PAI-1), CRP, platelet count, disease activity score (DAS28) and a marker of oxidative stress, 8-iso-prostaglandin F2alpha (r from -0.44 to -0.79; all, p<0.0001). Similar positive associations were found for clot lysis time (r 0.44 to 0.69; all, p<0.01). Multiple regression analysis showed that fibrinogen was the only independent predictor of clot permeability (R2=0.87, p<0.0001) and lysis time (R2=0.80, p<0.003) in RA. Maximum D-dimer levels released from clots, maximum clot turbidity and the time of clot formation were predicted by PAI-1 (all, p<0.05). CONCLUSION: We showed unfavorably altered plasma fibrin clot structure and function in RA, which might contribute to an increased risk of thrombotic events in this disease.

Thrombin generation in rheumatoid arthritis: dependence on plasma factor composition.

Growing evidence indicates that rheumatoid arthritis (RA) is associated with an increased risk for thromboembolic cardiovascular events. We investigated thrombin generation profiles in RA patients and their dependence on plasma factor/inhibitor composition. Plasma factor (F) compositions (II, V, VII, VIII, IX, X), antithrombin and free tissue factor pathway inhibitor (TFPI) from 46 consecutive RA patients with no cardiovascular events (39 female, 7 male, aged 57 [range, 23-75] years; DAS28 [Disease Activity Score] 5.2 +/- 1.1) were compared with those obtained in age- and sex-matched apparently healthy controls. Using each individual's plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed both computationally and empirically. RA patients had higher fibrinogen (4.18 [IQR 1.09] vs. 2.56 [0.41] g/l, p<0.0001), FVIII (226 +/- 40 vs. 113 +/- 15%, p<0.001), PC (107 [16] vs. 100 [14]%, p<0.001), and free TFPI levels (22.3 [2.2] vs. 14.7 [2.1] ng/ml, p<0.001). DAS28, but not age, RA duration, or C-reactive protein, was associated with FV, FVIII, FIX, FX, antithrombin, and free TFPI (r from 0.27 to 0.48, p<0.05). Intergroup comparison of computational thrombin generation profiles showed that in RA patients, maximum thrombin levels (p=0.01) and the rate of thrombin formation (p<0.0001) were higher, whereas the initiation phase of thrombin generation (p<0.0001) and the time to maximum thrombin levels (p<0.0001) were longer. Empirical reconstructions of the populations reproduced the thrombin generation profiles generated by the computational model. Simulations of thrombin formation suggest that blood plasma composition, i.e. a marked increase in FVIII, somewhat counterbalanced by free TFPI, contributes to the prothrombotic phenotype in RA patients.