Veli Cobankara

Heart rate variability in patients with rheumatoid arthritis

Heart rate variability (HRV) is a useful tool for the detection of sympathetic-parasympathetic balance in the autonomic nervous system. Autonomic nervous system involvement in patients with rheumatoid arthritis (RA) has rarely been studied and has shown conflicting results. Our purpose was to determine if HRV showed changes in patients with RA in comparison with the normal population. Short-term analysis of HRV was performed for time-domain frequency in 42 patients with RA and 44 matched controls. In this analysis, patients displayed lower standard deviation of the mean than healthy subjects (P<0.0001). Patients tended to display higher pNN50 and root-mean-square of successive difference values than did healthy subjects, but these differences were not statistically significant (P>0.05). In frequency domain analysis, the spectral measures of HRV showed reduced high-frequency (HF) values and an higher low-frequency (LF) values; as a result, the ratio between low and high frequencies (LF/HF), representative of sympathovagal modulation, was significantly increased (P=0.001, P=0.012, and P=0.003, respectively). Our data suggest an increase in sympathetic control of the heart rate in patients with RA. This increased sympathetic activity could play a key role in the development of ventricular tachyarrhythmias in RA and may be related to the higher incidence of sudden death in this disorder.

Identification of multiple genetic susceptibility loci in Takayasu arteritis

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).

Takayasu's arteritis is associated with HLA-B*52, but not with HLA-B*51, in Turkey

IntroductionHLA-B*51 and HLA-B*52 are two close human leukocyte antigen (HLA) allele groups with minor amino acid differences. However, they are associated with two different vasculitides (HLA-B*51 in Behçets disease and HLA-B*52 in Takayasus arteritis (TAK)) and with major clinical and immunological differences. In this study, we aimed to screen a large cohort of TAK patients from Turkey for the presence of HLA-B*51 and HLA-B*52 as susceptibility and severity factors.MethodsTAK patients (n = 330) followed at a total of 15 centers were included in the study. The mean age of the patients was 37.8 years, and 86% were women. DNA samples from the patients and healthy controls (HC; n = 210) were isolated, and the presence of HLA-B*51 or HLA-B*52 was screened for by using PCR with sequence-specific primers.ResultsWe found a significant association of HLA-B*52 with TAK (20.9% vs HC = 6.7%, P = 0.000, OR = 3.7, 95% CI = 2.02 to 6.77). The distribution of HLA-B*51 did not differ between TAK patients and HCs (22.7% vs 24.8%, OR = 0.9, 95% CI = 0.60 to 1.34). The presence of HLA-B*52 decreased in late-onset patients (> 40 years of age; 12.0%, P = 0.024, OR = 0.43, 95% CI = 0.20 to 0.91). Patients with angiographic type I disease with limited aortic involvement also had a lower presence of HLA-B*52 compared to those with all other disease subtypes (13.1% vs 26%, P = 0.005, OR = 0.43, 95% CI = 0.23 to 0.78).ConclusionsIn this study, the previously reported association of TAK with HLA-B*52 in other populations was confirmed in patients from Turkey. The functional relevance of HLA-B*52 in TAK pathogenesis needs to be explored further.

Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study

Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome‐wide association analysis of Takayasu arteritis.

Renin and angiotensin-converting enzyme (ACE) as active components of the local synovial renin-angiotensin system in rheumatoid arthritis

Local functional renin-angiotensin systems (RAS) have been demonstrated in many organ and tissue systems. Angiotensins, the effector growth factors of the RAS, are essentially cytokines and growth factors which actively contribute to many inflammatory reactions. Among the components of RAS, angiotensin-converting enzyme (ACE) and renin have been previously investigated separately in RA. In this study, ACE levels and renin concentrations were measured in the sera of 16 patients with RA (median age: 45 (26–69), male/female: 3/13), 13 patients with osteoarthritis (OA) (median age: 55 (28–72), male/female: 5/8), and 11 healthy adults (median age: 44 (35–70), male/female: 6/5). Synovial ACE levels and renin concentrations were also measured concurrently in patients with RA and OA. Serum ACE levels were comparable between the groups. However, synovial fluid ACE levels were significantly higher in the patients with RA than in patients with OA. Likewise, synovial fluid renin concentrations were higher in RA patients than in OA patients, while serum renin concentrations were similar in patients with RA and OA and in healthy controls. Moreover, there was a significant negative correlation between the duration of the disease and synovial renin concentrations in RA patients. In conclusion, locally-generated active renin and ACE could contribute to joint destruction in rheumatoid arthritis.

Incidence of Cyclophosphamide-induced Urotoxicity and Protective Effect of Mesna in Rheumatic Diseases

Objective. To assess bladder toxicity of cyclophosphamide (CYC) and uroprotective effect of mesna in rheumatic diseases. Methods. Data of 1018 patients (725 women/293 men) treated with CYC were evaluated in this retrospective study. All of the following information was obtained: the cumulative CYC dose, route of CYC administration, duration of therapy, concomitant mesna usage, and hemorrhagic cystitis. Cox proportional hazard model was used for statistics. Results. We identified 17 patients (1.67%) with hemorrhagic cystitis and 2 patients (0.19%) with bladder cancer in 4224 patient-years. The median time for diagnosis to hemorrhagic cystitis was 10 months (4–48) and bladder cancer was 8 years (6–10.9). There were 583 patients (57.2%) who received mesna with intravenous CYC therapy. We observed similar incidence rate for hemorrhagic cystitis in both patient groups concomitantly treated with or without mesna [9/583 (1.5%) vs 8/425 (1.8%) respectively, p = 0.08]. Cumulative CYC dose (HR for 10-g increments 1.24, p < 0.001) was associated with hemorrhagic cystitis. Conclusion. Cumulative dose was the only risk factor for hemorrhagic cystitis in patients treated with CYC. No proof was obtained for the uroprotective effect of mesna in our cohort.

Effect of infliximab treatment on QT intervals in patients with ankylosing spondylitis.

Background Cardiovascular complications are one of the most common and the most serious extraskeletal manifestations of ankylosing spondylitis (AS). Infliximab, a monoclonal antibody against tumor necrosis factor, is widely used in the treatment of AS. QT dispersion (QTd), which relates to left ventricular function and is used as an index of cardiac dysrhythmia, may be useful as a prognostic guide. Early detection of possible cardiac involvement may not be clinically evident, whereas it may be detected by electrocardiography. Objectives The aim of this prospective study was to assess the effect of infliximab treatment on QT intervals in patients with AS. Methods Twenty-one patients (17 females and 4 males) with AS who were in the active phase of disease (Bath Ankylosing Spondylitis Disease Activity Index score >4) were enrolled in the study. Infliximab was administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and every 6 weeks thereafter. QT intervals were recorded before and after 6 months of treatment. Results QT corrected (QTc) for heart rate was significantly reduced in the patients with AS after 6 months of infliximab therapy (406 ± 5.5 vs 388 ± 6.6 milliseconds; P = 0.029). There was no difference in the QTc dispersion (34.3 ± 11.1 vs 34.1 ± 8.6; P = 0.171). Body mass index and lipid profile were slightly increased after the treatment, but the difference was statistically insignificant. Conclusion Inflammation can affect the ventricles with an unknown mechanism, and QTc may be slightly prolonged as a result in the active phase of AS. In our study, QTc was shortened under infliximab therapy by suppressing inflammation. Therefore, this effect may protect patients with AS from fatal arrhythmias and sudden cardiac death.

Successful treatment of rheumatoid arthritis is associated with a reduction in serum sE-selectin and thrombomodulin level

The aim of this study was to investigate the changes in serum levels of endothelial cell injury markers, soluble (s) E-selectin and thrombomodulin (TM), in patients with rheumatoid arthritis (RA) before and after antirheumatic drug treatment and to assess the relationship between these changes and clinical responses to the drug treatment. Eleven patients with RA having active arthritis and 12 healthy volunteers were enrolled in the study. They were monitored by clinical and laboratory parameters while receiving a combination of methotrexate, hydroxychloroquine and sulphasalazine. Pre- and post-treatment clinical and laboratory parameters, including sE-selectin and sTM levels, were measured. The ages of the patients were comparable with those of the control groups. Significant improvements were detected in erythrocyte sedimentation rate, C-reactive protein, hemoglobin, morning stiffness, patients’ global assessment, physicians’ global assessment, number of tender joints and number of swollen joints improved at the end of the therapy (for each parameter p<0.05). Significant improvements were detected in clinical and laboratory parameters. In the patient group there were significant decreases in the levels of sTM and sE-selectin after treatment (p<0.05). The patient group had significantly higher sTM and sE-selectin levels than the control group at the beginning of the study (p<0.01), but the difference returned to normal after the treatment (p>0.05). The sE-selectin and sTM levels significantly correlated with each other, and also with clinical and laboratory findings. Combination treatment successfully treated RA patients. sE-selectin and sTM levels probably reflect disease activity and can be helpful in monitoring disease status and response to therapy.

Characteristics Predicting Tuberculosis Risk under Tumor Necrosis Factor-α Inhibitors: Report from a Large Multicenter Cohort with High Background Prevalence

Objective. Screening strategies for latent tuberculosis (TB) before starting tumor necrosis factor (TNF)-α inhibitors have decreased the prevalence of TB among patients who are treated with these agents. However, despite vigilant screening, TB continues to be an important problem, especially in parts of the world with a high background TB prevalence. The aim of this study was to determine the factors related to TB among a large multicenter cohort of patients who were treated with anti-TNF. Methods. Fifteen rheumatology centers participated in this study. Among the 10,434 patients who were treated with anti-TNF between September 2002 and September 2012, 73 (0.69%) had developed TB. We described the demographic features and disease characteristics of these 73 patients and compared them to 7695 patients who were treated with anti-TNF, did not develop TB, and had complete data available. Results. Among the 73 patients diagnosed with TB (39 men, 34 women, mean age 43.6 ± 13 yrs), the most frequent diagnoses were ankylosing spondylitis (n = 38) and rheumatoid arthritis (n = 25). More than half of the patients had extrapulmonary TB (39/73, 53%). Six patients died (8.2%). In the logistic regression model, types of anti-TNF drugs [infliximab (IFX), OR 3.4, 95% CI 1.88–6.10, p = 0.001] and insufficient and irregular isoniazid use (< 9 mos; OR 3.15, 95% CI 1.43–6.9, p = 0.004) were independent predictors of TB development. Conclusion. Our results suggest that TB is an important complication of anti-TNF therapies in Turkey. TB chemoprophylaxis less than 9 months and the use of IFX therapy were independent risk factors for TB development.

Diagnostic dilemma of paraneoplastic arthritis: case series.

Paraneoplastic arthritis (PA) may mimic rheumatic diseases. While presenting the demographic and laboratory features of the patients diagnosed with PA, this study also aims to provide possible appropriate tools to differentiate the PA cases from early rheumatoid arthritis (ERA).