Accelerated atherosclerosis in premenopausal women with rheumatoid arthritis - 15-year follow-up.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased mortality and morbidity due to the higher cardiovascular risk in these patients. Traditional risk factors are not the only answer for the accelerated atherosclerosis. In a long-term prospective study, we investigated the relationship between asymptomatic atherosclerosis and traditional risk factors and inflammatory markers in patients with RA and matched healthy controls. We studied the laboratory test results, the concentrations of inflammatory mediators, matrix metalloproteases (MMP), and inflammation markers in a total of 70 (60 at follow-up) premenopausal healthy women with RA and 40 (34 at follow-up) matched controls. We used the B-mode ultrasound imaging of carotid arteries for the detection of asymptomatic atherosclerosis. Correlation with different factors was evaluated. Statistically significant higher values of inflammatory markers such as selective adhesion molecules ICAM and VCAM, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and MMP-3 in the patients group were found in the follow-up study. More plaques were found in the patients group (42.4% vs. 12.9%; p=0.005), as compared with the controls group. The patients had also higher values of cIMT (p=0.001). Using bivariate regression analysis only VCAM was found as a prognostic factor for plaque occurrence (r= 0. 341, p=0.016), but not for cIMT (r= -0.130, p=0.327) in premenopausal female patients with RA after the follow-up. Therefore, asymptomatic atherosclerosis is accelerated in premenopausal women with RA. The results of our follow-up study showed the association between inflammation and accelerated atherosclerosis. Furthermore, VCAM was found to have a statistically significant correlation with plaque occurrence in these patients.

STAT signaling as a marker of SLE disease severity and implications for clinical therapy.

The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). While small-molecule JAK inhibitors (Jakinibs) are currently under investigation for SLE, results of recent studies suggest, that the efficacy of drugs such as methotrexate (MTX) may also be due to their ability to suppress phosphorylation of STAT proteins. A previously identified STAT5 phosphorylation (pSTAT5) and STAT1 protein expression ¼signature« in circulating CD4+ T cells of patients with SLE was associated with perturbed homeostasis between conventional (Tcon) and activated regulatory (aTreg) subset and with time-adjusted cumulative disease activity during follow-up. Initial observations in SLE patient cohort were validated with additional markers of disease severity and patients were stratified according to medication status. Preliminary results show that lower CD4+ T-cell counts in patients with SLE are associated with higher pSTAT5 levels and Tcon homeostatic proliferation, which was previously found to drive lymphopenia associated autoimmunity. Relapsing disease was better predicted by pSTAT5 levels than CD4 counts. Further, significant correlation was found between mean pSTAT5 levels during follow- up and the markers of disease severity. As patients with SLE, also patients with rheumatoid arthritis (RA) not receiving methotrexate, had significantly higher increase in CD4+ T-cell pSTAT5 levels compared to patients not receiving this specific therapy. However, the difference in pSTAT5 between Tcon and aTreg was independent of treatment with MTX and significantly increased only in patients with SLE. CD4 depletion, driving homeostatic proliferation of Tcon subset, is therefore associated with higher pSTAT5 levels, which confer worse prognosis in patients with SLE. While treatment with MTX may decrease overall pSTAT5 levels in CD4+ T-cells also from patients with RA, increased pSTAT5 levels in Tcon relative to aTreg subset are specific for SLE.

[Spectral Domain Optical Coherence Tomographic Findings in Systemic Lupus erythematosus in Patients Treated with Chloroquine]. / Ergebnisse spektraler optischer Kohärenztomografie bei den mit Chloroquin behandelten Patienten mit systemischem Lupus erythematodes.

PURPOSE: To recognise possible retinal changes in patients with SLE treated with chloroquine phosphate, as depending on the duration of treatment. METHODS: The study included 41 patients (82 eyes) who received treatment for SLE with chloroquine or hydroxychloroquine phosphate and had not previously been diagnosed with retinal pathology. Participants were divided into two groups according to the duration of treatment. The first group included 18 patients (36 eyes) treated for up to five years and the second group consisted of 23 patients (46 eyes) treated from five to twenty years. We performed a thorough eye exam, including best-corrected visual acuity, colour vision, visual field examination, dilated fundus examination, autofluorescence imaging, color fundus photography and spectral domain optical coherence tomography. RESULTS: Mean duration of treatment in the first group was 2.79 ± 1.37 years, and in the second group 8.67 ± 2.26 years. The difference in central retinal thickness between the two groups was not statistically significant (p > 0.05). Comparison of parafoveal thickness between the two groups was statistically non-significant in all quadrants (p > 0.05). Visual field examination, autofluorescence images and colour fundus photographs were without noteworthy pathology. CONCLUSION: Our results indicate that there were no significant changes in retinal structure between groups that depended on the duration of treatment. Hence, we can conclude that a yearly follow-up of these patients is sufficient to discover possible preclinical maculopathy.

HPLC-MS/MS method optimisation for matrix metalloproteinase 3 and matrix metalloproteinase 9 determination in human blood serum using target analysis.

A quantitative analysis of zinc endopeptidases matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 3 (MMP3) from human blood serum are presented. Both matrix metalloproteinases (MMP) are present in human blood serum and can be used as biomarkers for different diseases. The analysis was performed using LC-MS/MS with a triple quadrupole mass spectrometer, based on two specific peptides of each MMP in comparison with an enzyme-linked immunosorbent assay (ELISA). While the conditions for the LC-MS/MS analysis of MMP9 peptides were previously reported for bronchoalveolar lavage fluid, the analysis of MMP3 peptides was newly quantified for human blood serum herein for the first time. For MMP3, the linear behaviour was determined in the concentration range from 1.0-200.0ng/mL (R2=0.997) with an LLOD of 0.5ng/mL. For MMP9, linearity was determined in the concentration range from 6.5-65.0ng/mL (R2=0.995) with an LLOD of 2.0ng/mL.

Opportunities and challenges in rheumatology research in Central Europe.

The Central European Congress of Rheumatology (CECR) has been organized by seven Central European countries: Austria, Croatia, Czech Republic, Hungary, Poland, Slovakia, and Slovenia. These countries have lots of similarities, but also differences, with respect to rheumatology research. In this paper, based on questionnaires, we wish to demonstrate achievements and difficulties in rheumatology research performed in our region.

[Development of Non-Arteritic Anterior Ischaemic Optic Neuropathy in the Initially Unaffected Fellow Eye in Patients Treated with Systemic Corticosteroids]. / Entwicklung einer nicht arteriitischen anterioren ischämischen Optikusneuropathie am ursprünglich gesunden Partnerauge bei den mit systemischen Kortikoidenbehandelten Patienten.

Background The objective of this prospective pilot study was to evaluate the results of systemic corticosteroid therapy in patient with non-arteritic anterior ischaemic neuropathy of the optical nerve (NAION) for an observation period of one year and to measure the NAION incidence in the initially healthy contralateral eye of these patients. Patients and Methods All patients diagnosed with acute NAION who were admitted to our ward during 2014 and who fulfilled all inclusion criteria for systemic corticosteroid therapy were included in the study. The inclusion criteria were corrected visual acuity of 0.3 or less and duration of illness of less than 2 weeks. All patients were examined by a rheumatologist and given a complete ophthalmological examination, including fluorescein angiography and examination of the visual field. Only 3 of the 23 patients fulfilled our inclusion criteria for corticoid treatment and were then treated. 10 patients served as controls. The treatment plan started with an initial dose of 80 mg prednisolone during the first two weeks. The dose was then tapered over 3 to 4 months. Results The mean best corrected visual acuity on admission was 0.12 and 0.35 after one year. The mean duration of treatment was 3.3 months. Treatment was discontinued after 5 to 6 months or 8 to 9 months after the initial examination. All patients then developed NAION on the contralateral eye. The mean visual acuity on the contralateral eye was 0.73. After 4 month follow-up, the visual acuity in two patients had decreased to 1.0 and in one patient was reduced from 0.8 to 0.4. No steroid treatment was initiated for the contralateral eye. No NAION was found in the contralateral eye in the control group. Conclusion Corticosteroid treatment improved vision in all patients with NAION in comparison with the untreated contralateral eye. In a single patient, visual acuity decreased in the contralateral eye. Our study confirmed that corticosteroid treatment may be a predisposing factor for the development of NAION am in the contralateral eye. Additional studies with more patients are needed to confirm our results.

STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity.

Activation of the STAT5 signaling pathway up-regulates antiapoptotic protein Bcl2 and drives proliferation of autoreactive conventional CD4 T cells (Tcons). In systemic lupus erythematosus (SLE), an increased T cell Bcl2 content and perturbed homeostasis of CD45RA-FOXP3hi activated regulatory T cells (aTregs) were described. We assessed Tcon/Treg subsets and phosphorylation of STAT5 (pSTAT5) in blood T cells from patients with SLE by using conventional and imaging flow cytometry. Forty-one patients with SLE, 33 healthy controls, and 29 patients with rheumatoid arthritis were included. Long-term monitoring was performed in 39 patients with SLE, which were followed longitudinally for up to 1000 d. Significantly increased Bcl2 protein content in T cells from patients with SLE was associated with IL-7-dependent STAT5 activation, expressed as increased basal levels and nuclear localization of pSTAT5. pSTAT5 levels were significantly increased in the FOXP3 low-expressing CD4+ T cell subsets but not in the aTreg subset, which was significantly decreased in patients with SLE. In contrast to aTreg, SLE Tcon displayed significantly increased pSTAT5 and Bcl2 levels. Moreover, the percentage of Tcon-expressing proliferation marker Ki-67 was significantly increased in patients with SLE and was positively correlated with CD4 T cell pSTAT5 levels. Finally, a subgroup of patients characterized by an increased Tcon-pSTAT5/aTreg-pSTAT5 ratio experienced a more aggressive-relapsing disease course and displayed higher time-adjusted cumulative CD4 T cell pSTAT5 levels during follow-up, which were positively correlated with time-adjusted cumulative disease activity. Our results indicate that imbalanced STAT5 phosphorylation, which is related to Bcl2 and Ki-67 expression, may confer survival and proliferative advantage to Tcon over aTreg and could represent a possible marker of SLE disease severity.

Increased Levels of STAT1 Protein in Blood CD4 T Cells from Systemic Lupus Erythematosus Patients Are Associated with Perturbed Homeostasis of Activated CD45RA-FOXP3hi Regulatory Subset and Follow-Up Disease Severity.

In murine systemic lupus erythematosus (SLE), aberrant regulation of interferon (IFN)-alpha-STAT1 signaling and perturbed homeostasis of CD4+FOXP3+ regulatory T cells (Tregs) were described. In the present study, STAT1 signaling and circulating Treg subsets were assessed by flow cytometry in 39 SLE patients and their potential association with disease course was examined during long-term follow-up. Levels of STAT1 protein as measured by median fluorescence intensity (MFI) were significantly increased in SLE CD4 T cells when compared with rheumatoid arthritis patients and healthy controls and were positively correlated with disease activity. The highest STAT1 MFI was found in CD45RA-FOXP3hi-activated Treg (aTreg) subset, which demonstrated the highest STAT1 phosphorylation responses among SLE CD4 T cells and significant decrease in proliferation marker Ki-67 expression after IFN-alpha stimulation. Percentage of Ki-67+ aTregs was significantly decreased in SLE patients and was negatively correlated with CD4 T cell STAT1 MFI. A subgroup of SLE patients characterized by lower aTreg counts experienced more severe relapsing disease course during 1,000 days of follow-up. Mean CD4 T cell STAT1 MFI in follow-up samples from SLE patients was negatively correlated with mean of follow-up aTreg counts. Our findings indicate that augmented STAT1 signaling may be involved in perturbed aTreg homeostasis, which could represent a possible marker of SLE disease severity.

Antiphospholipid antibodies and atherosclerosis: insights from rheumatoid arthritis--a five-year follow-up study.

OBJECTIVES: Life expectancy in rheumatoid arthritis (RA) patients is reduced by 3-10 years, probably due to cerebrovascular and cardiovascular diseases associated with atherosclerosis. In the present study, we wanted to verify if previously reported IgA anti-beta 2-glycoprotein I (2GPI) antibodies possibly represented an independent risk factor for atherosclerosis in RA patients during a longer period of follow up. METHODS: The follow-up study (after 5.5 years) comprised all initially included patients and controls (premenopausal women, non-diabetic, normotensive at the start of the study), except for two RA patients (one died and one not available). The same clinical, laboratory and ultrasound assessments were performed. RESULTS: Patients and controls were divided into three categories: Intima-media thickness (IMT) progressors, plaque progressors, IMT and plaque progressors. In controls, 55% represented IMT progressors and 5% IMT and plaque progressors. No statistically significant differences were detected comparing the progressors with delta (Δ=difference between follow-up and baseline study for each group in a time span of 5.5 years) LDL cholesterol, homocysteine and IgA anti-ß2GPI. In patients, there were 48.5% IMT progressors, 5.8% plaque progressors and 19.1% IMT and plaque progressors. The progression was statistically significant associated with the levels of Δ homocysteine and Δ apolipoprotein B but not with LDL cholesterol and IgA anti-ß2GPI. CONCLUSIONS: The follow-up study showed advanced atherosclerosis in RA patients compared to sex and age matched controls. However, we were not able to confirm our initial impression that IgA anti-ß2GPI might represent an independent risk factor for atherosclerosis.

Antiphospholipid antibodies as a possible risk factor for atherosclerosis in patients with rheumatoid arthritis.

Atherosclerosis shares many similarities with inflammatory and autoimmune diseases, among them rheumatoid arthritis (RA). Anticardiolipin antibodies (aCL) and antibodies against beta2-glycoprotein I (anti-beta2GPI) have been detected in sera of RA patients in several studies. We demonstrated aCL and anti-beta2GPI in a selected group of 70 patients with RA (premenopausal women, non-diabetic, non-hypertensive) and compared them with age- and sex-matched controls. There was a significant higher internal carotid artery intima-media thickness and number of plaques in RA patients compared to controls. aCL of IgG and IgM classes were present in 15.7% of RA patients as compared to 5% in the control group. Thirty percent of RA patients had anti-beta2GPI of IgG, IgM and IgA classes compared to 7.5% in controls. Major differences were seen in IgG and IgA classes. Our results support the idea that aCL and anti-beta2GPI represent an important risk factor for atherosclerosis in RA patients. Elevated levels of phosphatidylserine-dependent antiprothrombin antibodies did not contribute significantly to the general prevalence of antiphospholipid antibodies.

[Posterior capsule opacification after phacoemulsification in patients with rheumatoid arthritis]. / Posteriore Kapselopazifikation nach Phakoemulsifikation bei Patienten mit rheumatoider Arthritis.

PURPOSE: To assess the posterior capsule opacification (PCO) rate after phacoemulsification with polyacrylic intraocular lens (IOL) implantation in patients with rheumatoid arthritis (RA) compared with the controls, and to assess whether preoperative activity of RA is associated with a higher incidence of PCO. METHODS: 24 eyes of 20 RA patients operated in a period of 4 years were included in our study. A control group of 20 eyes from 20 health subjects were also included in our study. All procedures were performed by a single surgeon with the same surgical technique and postoperative medication. RESULTS: One year postoperatively in two eyes (8.3%) of RA-patients lens epithelial cells (LEC) migration of grade 1 was observed, in controls also in two eyes (10%). No correlation was observed between age, duration of RA or preoperative activity of RA and the PCO rate. CONCLUSION: Following acrylic IOL implantation, the PCO rate one year after surgery was 8.3% in RA patients and 10% in controls. RA patients present no higher risk for PCO development than controls.