Association between PYTPN22 rs2476601, VEGF rs833070, TNFAIP3 rs6920220 Polymorphisms and Risk for Rheumatoid Arthritis in Early Undifferentiated Arthritis Patients: A Pilot Study.

Background and Objectives: About 40% of early undifferentiated arthritis (UA) progresses to rheumatoid (RA) or other chronic arthritis. Novel diagnostic tools predicting the risk for this progression are needed to identify the patients who would benefit from early aggressive treatment. Evidence on the role of single-nucleotide polymorphisms (SNPs) in the development of RA has emerged. The aim of our study was to investigate the association between rs2476601, rs833070, and rs6920220 SNPs and UA progression to RA. Materials and Methods: Ninety-two UA patients were observed for 12 months. At study entry, demographic and clinical characteristics were recorded, musculoskeletal ultrasonography was performed, and blood samples were drawn to investigate levels of inflammatory markers, rheumatoid factor (RF), anti-citrullinated protein antibodies (anti-CCP)detect SNPs. After 12 months, UA outcomes were assessed, and patients were divided into two (RA and non-RA) groups. The association between the risk of progression to chronic inflammatory arthritis and analyzed SNPs was measured by computing odds ratios (OR). Results: After a 12-month follow-up, 27 (29.3%) patients developed RA, and 65 (70.7%) patients were assigned to the non-RA group. The arthritis of 21 patients (22.8%) from the non-RA group resolved completely, while the other 44 (47.2%) patients were diagnosed with another rheumatic inflammatory disease. The patients who developed RA had a significantly greater number of tender and swollen joints (p = 0.010 and p = 0.021 respectively) and were more frequently RF or anti-CCP (p < 0.001), and both RF and anti-CCP positive (p < 0.001) at the baseline as compared with the patients in the non-RA group. No significant association between rs2476601 (OR = 0.99, p = 0.98), rs833070 (OR = 1.0, p = 0.97), and rs6920220 (OR = 0.48, p = 0.13) polymorphisms and the risk of developing RA were found. Conclusions: No association between analyzed SNPs and a greater risk to progress from UA to RA was confirmed, although patients with rs6920220 AA + AG genotypes had fewer tender joints at the disease onset.

VEGF Profile in Early Undifferentiated Arthritis Cohort.

Background and Objectives: Early undifferentiated arthritis (UA) is a group of inflammatory joint diseases that are not classified under any specific rheumatic or connective tissue disorder and might evolve into chronic inflammatory arthritis or may be a self-limiting condition. Early recognition and treatment are crucial for the future course of the disease. Vascular endothelial growth factor (VEGF) is an angiogenic regulator that induces the growth of new capillary blood vessels, which are important in joint invasion and destruction during the progression of chronic inflammatory arthritis. The aim of this study was to assess VEGF levels associated with sociodemographic, clinical, laboratory, and ultrasound findings in the early UA patient cohort as well as to evaluate VEGF as a potential prognostic marker for arthritis outcomes. Materials and Methods: Seventy-six patients with inflammatory arthritis in at least one joint, with a duration of arthritis <12 months at the study entry that did not meet any rheumatic disease classification criteria, were enrolled after informed consent was obtained. Patient's sociodemographic, laboratory data, and clinical disease characteristics were recorded, VEGF levels were measured, and ultrasound (US) of tender and swollen joints was performed. Results: VEGF levels had positive correlation with conventional rheumatic disease activity and diagnostic markers: erythrocyte sedimentation rate (ESR), C−reactive protein (CRP), and rheumatoid factor (RF) (p < 0.05). RF-positive patients had higher VEGF values (p = 0.024). A statistically higher number of patients whose VEGF levels were below the median value presented with active infection (p = 0.046). In patients with a higher number of swollen joints, and a higher score of synovitis and power doppler (PD) seen on US, VEGF levels were statistically significantly higher. Patients who after 12-month follow-up developed rheumatoid arthritis (RA) had statistically higher VEGF levels at baseline compared with those who developed spondyloarthropathies (p = 0.028). Conclusions: This study demonstrated that VEGF levels significantly represented inflammatory processes that were present in the joints (number of swollen joints, synovitis, and PD changes) of the early UA cohort.

The Expression of Inflammasomes NLRP1 and NLRP3, Toll-Like Receptors, and Vitamin D Receptor in Synovial Fibroblasts From Patients With Different Types of Knee Arthritis.

Activated rheumatoid arthritis (RA) synovial fibroblasts (SFs) are among the most important cells promoting RA pathogenesis. They are considered active contributors to the initiation, progression, and perpetuation of the disease; therefore, early detection of RASF activation could advance contemporary diagnosis and adequate treatment of undifferentiated early inflammatory arthritis (EA). In this study, we investigated the expression of nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing (NLRP)1, NLRP3 inflammasomes, Toll-like receptor (TLR)1, TLR2, TLR4, vitamin D receptor (VDR), and secretion of matrix metalloproteinases (MMPs) in SFs isolated from patients with RA, osteoarthritis (OA), EA, and control individuals (CN) after knee surgical intervention. C-reactive protein, general blood test, anticyclic citrullinated peptide (anti-CCP), rheumatoid factor (RF), and vitamin D (vitD) in patients' sera were performed. Cells were stimulated or not with 100 ng/ml tumor necrosis factor alpha (TNF-α) or/and 1 nM or/and 0.01 nM vitamin D3 for 72 h. The expression levels of NLRP1, NLRP3, TLR1, TLR2, TLR4, and VDR in all examined SFs were analyzed by quantitative real-time PCR (RT-qPCR). Additionally, the secretion of IL-1ß by SFs and MMPs were determined by ELISA and Luminex technology. The expression of NLRP3 was correlated with the levels of CRP, RF, and anti-CCP, suggesting its implication in SF inflammatory activation. In the TNF-α-stimulated SFs, a significantly lower expression of NLRP3 and TLR4 was observed in the RA group, compared with the other tested forms of arthritis. Moreover, upregulation of NLRP3 expression by TNF-α alone or in combination with vitD3 was observed, further indicating involvement of NLRP3 in the inflammatory responses of SFs. Secretion of IL-1ß was not detected in any sample, while TNF-α upregulated the levels of secreted MMP-1, MMP-7, MMP-8, MMP-12, and MMP-13 in all patient groups. Attenuating effects of vitD on the expression of NLRP3, TLR1, and TLR4 suggest potential protective effects of vitD on the inflammatory responses in SFs. However, longer studies may be needed to confirm or fully rule out the potential implication of vitD in SF activation in inflammatory arthritis. Both VDR and NLRP3 in the TNF-α-stimulated SFs negatively correlated with the age of patients, suggesting potential age-related changes in the local inflammatory responses.

The impact of anti-cyclic citrullinated peptide antibody status on the management of patients with early rheumatoid arthritis: observational study results from Lithuania.

BACKGROUND: To provide data on the use of anti-cyclic citrullinated peptide antibody (anti-CCP) and other routinely used clinical parameters and to assess the impact of anti-CCP status on therapeutic decisions, an observational study was conducted in patients with rheumatoid arthritis (RA). METHODS: Sixty-seven adult patients with a recent diagnosis of RA were recruited from four rheumatology centres in Lithuania and were prospectively observed for 12 months. Data collection was based on the review of medical records and routine examination of patients. Patients completed the Health Assessment Questionnaire - Disability Index and Patient Global Assessment of disease activity using a visual analogue scale. Physicians were asked about the importance of the anti-CCP results and other factors important for therapeutic decisions. RESULTS: Of the 67 patients enrolled, 54 (80.6%) completed the study. At the beginning of the study, physicians considered anti-CCP results to be important for decision-making in 87.0% of patients. The perceived importance of anti-CCP results did not change significantly throughout the study. After one year of treatment, factors that were considered more important than the anti-CCP results included the presence of erosions, significantly increased C-reactive protein, duration of morning stiffness, multi-articular expanding, and rheumatoid factor status. For nearly half of the patients (n = 26; 48.1%), physicians would not change the treatment strategy if the patient had the opposite anti-CCP results at baseline. CONCLUSIONS: The study revealed that decision-making in the management of RA was based on multifactorial data. The role of anti-CCP as a single test in treatment decisions needs further investigation.

The fact not to ignore: Mean blood pressure is the main predictor of increased arterial stiffness in patients with systemic rheumatic diseases.

PURPOSE: We aimed to evaluate the association between carotid-radial pulse wave velocity (PWV), augmentation index (AIx), and flow-mediated dilatation (FMD) of the brachial artery and factors potentially influencing them in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). MATERIAL AND METHODS: 316 patients diagnosed with RA (32%), SLE (20%), SSc (16%) and 156 controls (32%) were included in the study. Parameters of arterial stiffness AIx and PWV were obtained using applanation tonometry. FMD reflecting endothelial function was measured by ultrasound. RESULTS: AIx was increased in all three diseases (p<0.0001), but no differences were found between rheumatic diseases. In most of the RA cases PWV values were abnormal (on average by 0.52m/sec higher than in controls), while in SSc patients FMD values were diminished (p=0.006). Mean blood pressure (MBP) was the most consistent predictive factor in all three diseases, influencing both PWV and AIx, although patient age was also important in variation of AIx. The disease activity score (DAS28) was relevant only in RA patients. Furthermore, SLE disease activity index in SLE or Rodnan skin thickness score had no statistical significance in SSc and inflammatory markers. CONCLUSIONS: Both, PWV and AIx are dependent on MBP and age DAS28 may affect AIx in RA patients, while other disease or inflammatory markers are unlikely to have any effect. MBP is one of the main cardiovascular risk factors affecting the arterial stiffness in RA, SLE and SSc patients therefore controlling MBP in systemic rheumatic disease patients is mandatory.

Predictors of mortality in patients with rheumatoid arthritis in Lithuania: Data from a cohort study over 10 years.

BACKGROUND AND OBJECTIVE: Increased mortality and shorter survival among rheumatoid arthritis (RA) patients are recognized but not fully explained. This cohort study aimed to identify predictors of mortality among RA patients at a tertiary clinical setting. MATERIALS AND METHODS: Patients with RA were recruited during 1998-2003 and followed up until April 1, 2012, or death whichever happened first. Baseline variables included sociodemographic and disease characteristics, and comorbidities. Cox regression and hazard risk (HR) were computed to estimate risks for mortality. RESULTS: One hundred ninety-one patients were included into the study, 186 patients were eligible for the analysis and of these 131 patients (70.4%) completed the entire period of followed-up while 55 patients (29.6%) died. The average follow up period was equivalent to 9.24 year per person. A Cox regression model identified four major factors having an impact on survival. History of a stroke at baseline was identified as a major factor (HR=5.33; 95% CI, 2.13-13.32). Statistically significant risk factors were also age over 50 years (HR=4.59; 95% CI, 2.04-10.30); education less than 11 years (HR=3.3; 95% CI, 1.72-6.33) and angina pectoris (HR=1.98; 95% CI, 1.03-3.80). CONCLUSIONS: Higher age, lower education and cardiovascular comorbidities were identified as predictors of mortality in this prospective cohort study while disease-related variables were not independent predictors of mortality.

The association of fatigue, comorbidity burden, disease activity, disability and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the Quest-RA program.

OBJECTIVES: The aim is to assess the prevalence of comorbidities and to further analyse to which degree fatigue can be explained by comorbidity burden, disease activity, disability and gross domestic product (GDP) in patients with rheumatoid arthritis (RA). METHODS: Nine thousands eight hundred seventy-four patients from 34 countries, 16 with high GDP (>24.000 US dollars [USD] per capita) and 18 low-GDP countries (<24.000 USD) participated in the Quantitative Standard monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid conditions, fatigue (0-10 cm visual analogue scale [VAS] [10=worst]), disease activity in 28 joints (DAS28), and physical disability (Health Assessment Questionnaire score [HAQ]) were assessed. Univariate and multivariate linear regression analyses were performed to assess the association between fatigue and comorbidities, disease activity, disability and GDP. RESULTS: Overall, patients reported a median of 2 comorbid conditions of which hypertension (31.5%), osteoporosis (17.6%), osteoarthritis (15.5%) and hyperlipidaemia (14.2%) were the most prevalent. The majority of comorbidities were more common in high-GDP countries. The median fatigue score was 4.4 (4.8 in low-GDP countries and 3.8 in high-GDP countries, p<0.001). In low-GDP countries 25.4% of the patients had a high level of fatigue (>6.6) compared with 23.0% in high-GDP countries (p<0.001). In univariate analysis, fatigue increased with increasing number of comorbidities, disease activity and disability in both high- and low-GDP countries. In multivariate analysis of all countries, these 3 variables explained 29.4% of the variability, whereas GDP was not significant. CONCLUSIONS: Fatigue is a widespread problem associated with high comorbidity burden, disease activity and disability regardless of GDP.

Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study.

INTRODUCTION: Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. METHODS: The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. RESULTS: At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. CONCLUSIONS: Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

Physical inactivity in patients with rheumatoid arthritis: data from twenty-one countries in a cross-sectional, international study.

OBJECTIVE: Regular physical activity is associated with decreased morbidity and mortality. Traditionally, patients with rheumatoid arthritis (RA) have been advised to limit physical exercise. We studied the prevalence of physical activity and associations with demographic and disease-related variables in patients with RA from 21 countries. METHODS: The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) is a cross-sectional study that includes a self-report questionnaire and clinical assessment of nonselected consecutive outpatients with RA who are receiving usual clinical care. Frequency of physical exercise (>or=30 minutes with at least some shortness of breath, sweating) is queried with 4 response options: >or=3 times weekly, 1-2 times weekly, 1-2 times monthly, and no exercise. RESULTS: Between January 2005 and April 2007, a total of 5,235 patients from 58 sites in 21 countries were enrolled in QUEST-RA: 79% were women, >90% were white, mean age was 57 years, and mean disease duration was 11.6 years. Only 13.8% of all patients reported physical exercise>or=3 times weekly. The majority of the patients were physically inactive with no regular weekly exercise: >80% in 7 countries, 60-80% in 12 countries, and 45% and 29% in 2 countries, respectively. Physical inactivity was associated with female sex, older age, lower education, obesity, comorbidity, low functional capacity, and higher levels of disease activity, pain, and fatigue. CONCLUSION: In many countries, a low proportion of patients with RA exercise. These data may alert rheumatologists to motivate their patients to increase physical activity levels.

Rheumatoid arthritis in Lithuania: need for external help from the onset of disease.

PURPOSE: To estimate the burden of rheumatoid arthritis (RA) in Vilnius, Lithuania, the former socialist country in Eastern Europe, in terms of patients' need for help from other persons and to explore the factors which influence the need for physical help. METHOD: Some 537 patients with RA, registered in Vilnius, answered questions about socio-demographics, disease characteristics, categories of required help, the use of major appliances and adaptations, underwent a clinical examination and filled in the modified health assessment questionnaire (MHAQ) and arthritis impact measurement scale (AIMS). Logistic regression was used to assess which variables from those explored influenced the need for physical help. RESULTS: A total of 230 (42.9%) patients out of 537 were requiring help from other persons, and the proportion was equally high in all the disease duration categories. A quarter of the patients (25.1%) were classified to ACR III and IV functional impairment groups. In multivariate logistic regression model the risk to become dependent on external help ultimately depended on MHAQ (10.32 [CI 95% 6.57; 16.23], p < 0.001) but the use of joint stabilization measures (1.97 [CI 95% 1.06; 3.64], p < 0.01) and 28 tender joints count (1.02 [CI 95% 1.0; 1.06], p < 0.05) were also important. CONCLUSIONS: Nearly half of the patients reported being dependent on others and a quarter of patients were in definite need for that. The functional impairment is the most important risk factor, although identifying the group using joint stabilization measures routinely may be of practical value in order to define the risk group which may need the external help in future.

[Comparison of health-related quality of life between patients with rheumatic diseases and a control group]. / Reumatinemis ligomis serganciu ligoniu ir kontrolines grupes tiriamuju gyvenimo kokybes palyginimas.

OBJECTIVE: To compare the health-related quality of life between patients with rheumatoid arthritis and systemic lupus erythematosus and a control group. METHODS AND MATERIAL: Eighty-eight patients with rheumatoid arthritis, 40 patients with systemic lupus erythematosus and 40 women who did not suffer from any inflammatory joint disease (control group) participated in this comparative study. The questionnaires they completed included information about their sociodemographic status and comorbidities. Patients with rheumatoid arthritis and systemic lupus erythematosus were assessed for pain (visual analogical scale), extra-articular manifestations, and disease activity; also they completed questionnaires for the evaluation of physical function (Health Assessment Questionnaire--HAQ) and burden of arthritis (Arthritis Impact Measurement Scale). All groups under investigation completed the health-related quality questionnaire SF-36 (Medical Outcomes Study Short Form-36) validated in Lithuania. RESULTS: The study of health-related quality of life of women with rheumatic disease showed that patients with systemic lupus erythematosus had stronger pain (p=0.017). It was also found that the activity of patients with rheumatoid arthritis was more limited because of emotional problems (p=0.038). No significant differences were found in other areas of life quality. It was recognized that in comparison to other groups, the quality of life of the control group was better (p=0.000) from the point of view of physical activity, limitations of activity because of physical problems, pain, overall health status and social relations. The psychological status of the latter was undoubtedly worse. CONCLUSIONS: In this study it was found that all patients with rheumatoid arthritis and systemic lupus erythematosus had evaluated most of the aspects of health-quality very similarly. Significant differences have been determined when assessing pain and limitation of activity because of emotional problems. The health-related quality of life of the control group is definitely better than that of the rest in most aspects, except for the psychological one.

High work disability rate among rheumatoid arthritis patients in Lithuania.

OBJECTIVE: To evaluate labor force characteristics among patients with rheumatoid arthritis (RA) in Lithuania. To assess if Lithuania's transition from a state-planned to a free-market economy after 1990 changed the employment perspectives of patients with RA. METHODS: RA patients, age 16-65 years (n = 238), were randomly selected from the RA register in Vilnius. They completed questions about sociodemographics, working status, and disease characteristics, they underwent a clinical examination, and they completed the modified Health Assessment Questionnaire and the Short Form 36. RESULTS: Age- and sex-adjusted employment was 24.2% lower and work disability 51.7% higher in patients compared with the general population in Lithuania. After 10 years of disease, 48% of the patients had withdrawn from the labor force. In those with a paid job, the average sick leave in the past year was 31.9 days compared with the national average of 10.8 days. Although disease activity was not significantly different in employed compared with work-disabled patients, physical function and perceived quality of life (except general health) were worse among patients with work disability. The change in economic organization in 1990 was noted to increase the risk for work withdrawal by a factor of 2.75 (95% confidence interval 1.68-4.53). CONCLUSION: In Lithuania, the impact of RA on work disability is important. Although work disability in Lithuanian patients with RA seems more pronounced compared with reports from Western societies, variables associated with work disability are comparable. The transition to a market-orientated economy in 1990 increased the risk of becoming work disabled.

[Anticitrulline antibodies - new marker in rheumatoid arthritis diagnostics]. / Anticitrulininiai antikunai - naujas reumatoidinio artrito diagnostinis zymuo.

The overview provides the knowledge about rheumatoid factor isotypes and their significance in the case of rheumatoid arthritis. New immunological methods have been introduced in the last decade proving their validity in seronegative rheumatoid arthritis. Antikeratin and anticitrulline antibodies were found to be useful diagnostic tools for seronegative and early rheumatoid arthritis. The methods perform well for scientific needs as well as in daily clinical practice.