Clinical and Hematological Effects of Tocilizumab on Serum Hepcidin, Anemia Response and Disease Activity in Patients with Active Rheumatoid Arthritis

OBJECTIVE: The purpose of this study is to evaluate the clinical and hematological effects of tocilizumab in active rheumatoid arthritis (RA) patients. METHODS: Fourteen patients with active RA were enrolled in this study. The patients received tocilizumab 8 mg/kg intravenously every four weeks for 6 months. Disease activity, anemia-related factors including serum hepcidin-25, and hematological parameters were monitored at baseline and at 1, 3, and 6 months after the initiation of treatment. RESULTS: Significant reductions in tender joint count, swollen joint count, visual analogue scale, erythrocyte sedimentation rate (ESR), and C-reactive (CRP) protein plus reductions in a 28-joint disease activity score were observed within one month after the first tocilizumab treatment. These effects lasted throughout the six-month study period. In addition, significant improvements in anemia-related factors such as hepcidin-25, ferritin, iron, hemoglobin, red blood cell counts and mean corpuscular volume were observed during the treatment period. Hematological parameters were improved with reductions in counts for leukocytes, monocytes, neutrophils, and platelets. The lymphocyte counts and their subset numbers were unchanged. Changes in hepcidin levels showed significant correlation with changes in CRP, ESR, ferritin, hemoglobin and counts for red blood cells, leukocytes, and neutrophils during the treatment period. CONCLUSION: This study demonstrates that tocilizumab significantly and meaningfully reduces disease burden in patients with active RA. In addition, tocilizumab diminishes the levels of inflammatory anemia by inhibiting hepcidin production. These clinical data provide evidence of a favorable outcome from tocilizumab in RA.

The Significance of Ectopic Germinal Centers in the Minor Salivary Gland of Patients with Sjogren's Syndrome

We investigated the clinical and biological significance of germinal centers (GC) present in the minor salivary glands of patients with Sjogren's syndrome (SS). Minor salivary gland tissue biopsies from 93 patients with SS were used to identify GC-like structures, which were confirmed by CD21-positive follicular dendritic cell networks. Patients were compared based upon sociodemographics, glandular and extraglandular manifestations, and laboratory findings including autoantibody profiles, complement, and immunoglobulin levels; EULAR SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) were also measured. GC-like structures were observed in 28 of 93 SS patients (30.1%). Mean focus scores and CRP levels were significantly higher in GC-positive patients than in GC-negative patients; GC-positive patients also exhibit a higher prevalence of rheumatoid factor and anti-SS-A/Ro antibodies compared to GC-negative patients. No differences in glandular or extra-glandular manifestations were evident between groups. In conclusion, SS patients with GC-like structures in the minor salivary glands exhibited laboratory profiles significantly different from those of their GC-negative counterparts. Long-term follow-up of these patients will be necessary to determine whether these laboratory abnormalities are predictive of clinical outcomes.

The Significance of Ectopic Germinal Centers in the Minor Salivary Gland of Patients with Sjogren's Syndrome

We investigated the clinical and biological significance of germinal centers (GC) present in the minor salivary glands of patients with Sjogren's syndrome (SS). Minor salivary gland tissue biopsies from 93 patients with SS were used to identify GC-like structures, which were confirmed by CD21-positive follicular dendritic cell networks. Patients were compared based upon sociodemographics, glandular and extraglandular manifestations, and laboratory findings including autoantibody profiles, complement, and immunoglobulin levels; EULAR SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) were also measured. GC-like structures were observed in 28 of 93 SS patients (30.1%). Mean focus scores and CRP levels were significantly higher in GC-positive patients than in GC-negative patients; GC-positive patients also exhibit a higher prevalence of rheumatoid factor and anti-SS-A/Ro antibodies compared to GC-negative patients. No differences in glandular or extra-glandular manifestations were evident between groups. In conclusion, SS patients with GC-like structures in the minor salivary glands exhibited laboratory profiles significantly different from those of their GC-negative counterparts. Long-term follow-up of these patients will be necessary to determine whether these laboratory abnormalities are predictive of clinical outcomes.

Chemokine (C-X-C Motif) Ligand 1 (CXCL1) Expression in the Minor Salivary Glands of Sjögren's Syndrome Patients

OBJECTIVE: To evaluate the laboratory and clinical manifestations of Sjögren's syndrome (SS) association with chemokine (C-X-C motif) ligand 1 (CXCL1) expression in the ductal and acinar salivary gland epithelial cells (SGEC) of the minor salivary glands. METHODS: The sociodemographic data of 106 SS patients was obtained, and the glandular and extraglandular manifestations of the disease documented. The minor salivary glands were biopsied and the laboratory findings analyzed. European League Against Rheumatism SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) scores were obtained during biopsy. An immunohistochemical approach was used to define the expression of CXCL1 in the salivary glands. RESULTS: Of 106 patients, the minor salivary glands of 22 patients (20.7%) stained positively for CXCL1. Such CXCL1-positive patients exhibited higher ESSDAI scores at the time of biopsy than the CXCL1-negative patients (3.86±2.27 vs. 2.64±1.62, p=0.015). Lymphadenopathy was more frequently observed in CXCL1-positive patients, compared with CXCL1-negative patients (31.8% vs. 9.5%, p=0.014). No differences between groups were identified in terms of sociodemographic characteristics, laboratory data, or the extent of the glandular manifestation of SS. CONCLUSION: The expression of CXCL1 within the ductal and acinar SGEC of SS patients is associated with lymphadenopathy and elevated clinical disease activity. CXCL1 may play an important role in the disease activity and prognosis of SS.

Usefulness of Cardiac Biomarkers in the Evaluation of Prognosis and Cardiac Involvement in Patients with Acute Aortic Syndrome

OBJECTIVE: To investigate the usefulness of cardiac biomarkers in the evaluation of prognosis and cardiac involvement (CI) in patients with acute aortic syndrome (AAS). METHODS: A total of 260 AAS patients with the measurements of cardiac biomarkers were divided into 2 groups; the survived (n=215, 60.6±13.7 years, 110 males) vs the dead (n=45, 64.5±13.6 years, 19 males). N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac specific troponin-I (cTnI), C-reactive protein (CRP), creatinine kinase (CK), MB fraction of CK (CK-MB), and D-dimer were compared. RESULTS: NT-proBNP and D-dimer were significantly elevated in the dead group than in the survived group (3558.7±5497.2 vs 949.9±2307.3 pg/mL, p<0.001, 4.5±5.1 vs 2.0±3.2 ug/mL, p<0.001, respectively). CI was observed in 59 patients (22.7%), and NT-proBNP was significantly elevated in patients with CI than in patients without CI (2497.7±4671.3 vs 722.5±1489.1 pg/mL, p=0.034). In univariate analysis, Stanford type A, CI, NT-proBNP, and D-dimer were significantly associated with mortality, but NT-proBNP was the only significant independent predictor of mortality in multivariate analysis. By receiver operating characteristic curve analysis, the optimal cut-off value to predict mortality was 517.0 pg/mL for NT-proBNP (area under the curve 0.797, sensitivity 86.7%, specificity 71.7%). CONCLUSION: The elevation of cardiac biomarkers is not infrequent in patients with AAS. NT-proBNP is significantly associated with CI and is an independent predictor of mortality in patients with AAS. The measurement of NT-proBNP would be useful in the risk stratification of AAS.

A Case of Sarcoidosis That Improved upon Discontinuation of Etanercept

A 31-year-old man who had been prescribed etanercept over a 3-year period for treatment of ankylosing spondylitis presented with newly developed dry cough, chills, myalgia, and weight loss. Chest computed tomography showed multiple reticulonodular pulmonary infiltrates and bilateral mediastinal, hilar, and peribronchial lymphadenopathy. Biopsy of a paratracheal lymph node revealed chronic granulomatous inflammation without necrosis, and the serum angiotensin-converting enzyme level was elevated. Sarcoidosis was diagnosed. His laboratory and radiological findings, and clinical symptoms improved only after discontinuation of etanercept without treatment. Although etanercept-induced sarcoidosis is rare, this case report suggests that sarcoidosis should be considered in the differential diagnosis of patients treated with the tumor necrosis factor inhibitor.

Exploring Genetic Susceptibility to Fibromyalgia / 전남의대학술지

Fibromyalgia (FM) affects 1% to 5% of the population, and approximately 90% of the affected individuals are women. FM patients experience impaired quality of life and the disorder places a considerable economic burden on the medical care system. With the recognition of FM as a major health problem, many recent studies have evaluated the pathophysiology of FM. Although the etiology of FM remains unknown, it is thought to involve some combination of genetic susceptibility and environmental exposure that triggers further alterations in gene expression. Because FM shows marked familial aggregation, most previous research has focused on genetic predisposition to FM and has revealed associations between genetic factors and the development of FM, including specific gene polymorphisms involved in the serotonergic, dopaminergic, and catecholaminergic pathways. The aim of this review was to discuss the current evidence regarding genetic factors that may play a role in the development and symptom severity of FM.

Exploring Genetic Susceptibility to Fibromyalgia / 전남의대학술지

Fibromyalgia (FM) affects 1% to 5% of the population, and approximately 90% of the affected individuals are women. FM patients experience impaired quality of life and the disorder places a considerable economic burden on the medical care system. With the recognition of FM as a major health problem, many recent studies have evaluated the pathophysiology of FM. Although the etiology of FM remains unknown, it is thought to involve some combination of genetic susceptibility and environmental exposure that triggers further alterations in gene expression. Because FM shows marked familial aggregation, most previous research has focused on genetic predisposition to FM and has revealed associations between genetic factors and the development of FM, including specific gene polymorphisms involved in the serotonergic, dopaminergic, and catecholaminergic pathways. The aim of this review was to discuss the current evidence regarding genetic factors that may play a role in the development and symptom severity of FM.

Effects of Valsartan on Carotid Arterial Stiffness in Patients with Newly Diagnosed Hypertension: A Comparative Study with Global Arterial Stiffness

BACKGROUND: To compare the parameters of local carotid stiffness with those of global arterial stiffness and to investigate the effects of angiotensin II receptor blocker (ARB) on the parameters of local carotid arterial stiffness as well as global arterial stiffness. METHODS: The correlations of the parameters between local carotid and global arterial stiffness were compared at baseline, and the changes of these parameters were evaluated after 6 months of valsartan therapy in 50 patients with newly diagnosed hypertension. Diameter change, strain, and 2-dimensional circumferential strain (2D CS) of the carotid artery measured by speckle tracking method were used as parameters of local arterial stiffness, and the parameters of pulse wave velocity (PWV) and pulse wave analysis (PWA) were used as standard parameters of global arterial stiffness. RESULTS: Carotid 2D CS, not conventional strain or diameter change, showed significant correlation with age (r = -0.592, p < 0.01), brachial-ankle PWV (r = -0.338, p < 0.05), and augmentation index (r = -0.298, p < 0.05). After 6 months of medical therapy, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were decreased significantly (SBP: 155.9 +/- 14.2 to 137.6 +/- 10.5 mm Hg, p < 0.01; DBP: 90.1 +/- 11.8 to 81.6 +/- 8.0 mm Hg, p < 0.01). The parameters of PWV and PWA were significantly improved, but the parameters of carotid arterial stiffness were not changed significantly. CONCLUSIONS: In hypertensives, carotid 2D CS showed better correlation with ageing and the parameters of global arterial stiffness than conventional strain or diameter change of the carotid artery. Global arterial stiffness was improved by 6 months of medical treatment with ARB, but the local carotid arterial stiffness was not changed.

Predictors of the Development of Significant Tricuspid Regurgitation after Permanent Pacemaker Implantation / 대한내과학회지

BACKGROUND/AIMS: We sought to identify predictors of significant tricuspid regurgitation (TR) after successful permanent pacemaker (PPM) implantation in Korean patients. METHODS: Of 404 patients who underwent PPM implantation, 187 patients who had both baseline and follow-up echocardiographic examinations were assigned to one of two groups: no development or change in TR (Group I, n = 172, 65.5 +/- 13.7 years) versus the development of significant TR (Group II, n = 15, 72.1 +/- 8.3 years). Clinical, laboratory, and echocardiographic variables were compared between the two groups. RESULTS: Overall, the grade of TR was significantly aggravated from 0.46 +/- 0.73 to 0.81 +/- 0.84 (p < 0.001) during 3.1 +/- 1.8 years of follow-up (0.49 +/- 0.75 to 0.69 +/- 0.74 in Group I, p < 0.001; 0.13 +/- 0.35 to 2.27 +/- 0.46 in Group II, p < 0.001). The de novo development or aggravation of TR was observed in 66 patients (35.3%), and significant TR developed in 15 patients (8.0%). The presence of atrial fibrillation (AF) was significantly higher (53.3 vs. 18.6%, p = 0.002), and the implantation of a ventricle pacing, ventricle sensing, inhibited by ventricular event (VVI) type pacemaker was more frequent in Group II than in Group I (46.7 vs. 15.1%, p = 0.002). Other variables were not different between the groups. CONCLUSIONS: The development or aggravation of TR was not rare after successful PPM implantation, even though the development of significant TR was uncommon. The presence of AF and the implantation of a VVI type pacemaker were predictors of the development of significant TR. Together, the results of this study suggest that the development or aggravation of TR should be monitored carefully after PPM implantation.

Successful Treatment of a Ruptured Subclavian Artery Aneurysm Presenting as Hemoptysis with a Covered Stent / 전남의대학술지

An aneurysm of the subclavian artery is rare. Recently, we experienced a case of a ruptured subclavian artery aneurysm presenting as hemoptysis. The patient had experienced atypical chest discomfort, and computed tomography (CT) revealed a small aneurysm of the left subclavian artery (SCA). Hemoptysis occurred 2 weeks later. Follow-up CT showed a ruptured aneurysm at the proximal left SCA. Endovascular treatment with a graft stent was performed by bilateral arterial access with a 12-Fr introducer sheath placed via cutdown of the left axillary artery and an 8-Fr sheath in the right femoral artery. A self-expandable Viabahn covered stent measuring 13x5 mm was introduced retrogradely via the left axillary sheath and was positioned under contrast guidance with an 8-Fr JR4 guide through the femoral sheath. After the procedure, hemoptysis was not found, and the 3-month follow-up CT showed luminal patency of the left proximal SCA and considerable reduction of the hematoma.

Successful Treatment of a Ruptured Subclavian Artery Aneurysm Presenting as Hemoptysis with a Covered Stent / 전남의대학술지

An aneurysm of the subclavian artery is rare. Recently, we experienced a case of a ruptured subclavian artery aneurysm presenting as hemoptysis. The patient had experienced atypical chest discomfort, and computed tomography (CT) revealed a small aneurysm of the left subclavian artery (SCA). Hemoptysis occurred 2 weeks later. Follow-up CT showed a ruptured aneurysm at the proximal left SCA. Endovascular treatment with a graft stent was performed by bilateral arterial access with a 12-Fr introducer sheath placed via cutdown of the left axillary artery and an 8-Fr sheath in the right femoral artery. A self-expandable Viabahn covered stent measuring 13x5 mm was introduced retrogradely via the left axillary sheath and was positioned under contrast guidance with an 8-Fr JR4 guide through the femoral sheath. After the procedure, hemoptysis was not found, and the 3-month follow-up CT showed luminal patency of the left proximal SCA and considerable reduction of the hematoma.

Differences of Aortic Stiffness and Aortic Intima-Media Thickness According to the Type of Initial Presentation in Patients with Ischemic Stroke

BACKGROUND: Aortic stiffness and intima-media thickness (IMT) are known to be associated with ischemic stroke. The aim of the present study was to investigate the differences of aortic stiffness and IMT between cerebral infarction (CI) and transient ischemic attack (TIA). METHODS: A total of 500 patients with acute stroke were divided into 2 groups: the TIA group (n = 230, 62.4 +/- 12 years, 144 males) versus CI group (n = 270, 63.4 +/- 11 years, 181 males). Aortic stiffness index and IMT, as well as conventional cardiovascular risk factors, were compared. RESULTS: The prevalence of hypertension, diabetes, and dyslipidemia were significantly higher, and left atrial volume and E/E' were significantly elevated in the CI group than in the TIA group. Carotid IMT was significantly thicker in the CI group than in the TIA group. Aortic stiffness index beta was significantly higher (7.99 +/- 2.70 vs. 7.02 +/- 4.30, p = 0.043) and aortic IMT was significantly thicker (1.53 +/- 0.41 vs. 1.45 +/- 0.39 mm, p = 0.040) in the CI group than in the TIA group. Aortic stiffness index beta was significantly correlated with the IMT of the aorta (r = 0.279, p = 0.014), right (r = 412, p < 0.001) and left carotid artery (r = 441, p < 0.001). CONCLUSION: Aortic stiffness index beta and IMT were significantly higher in patients with CI than TIA. The result of the present study suggested that CI is associated with more advanced degree of atherosclerotic and arteriosclerotic process than TIA.

Effects of Low Dose versus High Dose Statin Therapy on the Changes of Endothelial Function and Carotid Intima-Media Thickness in Patients with Variant Angina

BACKGROUND: To compare the effects of low dose and high dose of statin treatment on endothelial function and carotid intima-media thickness (IMT) in patients with variant angina (VAP). METHODS: A total of 70 patients with VAP were divided into two groups; atorvastatin 10 mg treatment group (group I: n = 35, 54.2 +/- 12.5 years) versus atorvastatin 40 mg treatment group (group II: n = 35, 52.6 +/- 9.8 years). Flow mediated vasodilation (FMD) of the brachial artery and IMT of the carotid artery were compared between the groups after 6 months of statin treatment. RESULTS: The baseline FMD and carotid IMT were not different between the groups. After 6 months of statin therapy, FMD was significantly improved in both groups (7.7 +/- 2.5% to 8.9 +/- 2.2% in group I, p = 0.001, 7.9 +/- 2.7% to 9.5 +/- 2.8% in group II, p < 0.001), but the degree of FMD change and FMD at 6 month were not different between the groups. Carotid IMT were not changed in both groups after 6 months of statin therapy. CONCLUSION: The use of statin for 6 months significantly improved endothelial function in patients with VAP, but carotid IMT was not changed. The use of high dose statin did not show significant additional benefit as compared with the use of low dose statin. The present study suggested that statin therapy would be beneficial in the treatment of VAP.