G. Ozen

Activation of the JAK/STAT pathway in Behcet’s Disease

Th1/Th17-type T-cell responses are upregulated in Behcet’s disease (BD). However, signaling pathways associated with this aberrant immune response are not clarified. Whole-genome microarray profiling was performed with human U133 (Plus 2.0) chips using messenger RNA of isolated CD14+ monocytes and CD4+ T cells from peripheral blood mononucleated cell (PBMC) in patients with BD (n=9) and healthy controls (HCs) (n=9). Flow cytometric analysis of unstimulated (US) and stimulated (phytohaemagglutinin) signal transducer and activator of transcription (STAT3) and pSTAT3 expressions of PBMCs were also analyzed (BD and HC, both n=26). Janus family of kinase (JAK1) was observed to be upregulated in both CD14+ monocytes (1.95-fold) and CD4+ T lymphocytes (1.40-fold) of BD patients. Using canonical pathway enrichment analysis, JAK/STAT signaling was identified as activated in both CD14+ monocytes (P=9.55E−03) and in CD4+ lymphocytes (P=8.13E−04) in BD. Interferon signaling was also prominent among upregulated genes in CD14+ monocytes (P=5.62E−05). Glucocorticoid receptor signaling and interleukin (IL-6) signaling were among the most enriched pathways in differentially expressed genes in CD14+ monocytes (P=2.45E−09 and 1.00E−06, respectively). Basal US total STAT3 expression was significantly higher in BD (1.2 vs 3.45, P<0.05). The JAK1/STAT3 signaling pathway is activated in BD, possibly through the activation of Th1/Th17-type cytokines such as IL-2, interferon (IFN-γ), IL-6, IL-17 and IL-23.

Right ventricular and atrial functions in systemic sclerosis patients without pulmonary hypertension

BackgroundSystemic sclerosis (SSc) is a systemic connective tissue disease and cardiac involvement is one of the most important causes of death. Right ventricular (RV) systolic dysfunction is a poor prognostic finding in SSc patients. Assessment of RV function has some difficulties because of its crescent shape and extensive trabeculations. Two-dimensional (2D) speckle-tracking echocardiography (STE) is an angle-independent quantitative technique to evaluate myocardial function. The aim of this study was to assess the RV and right atrial (RA) functions of SSc patients without pulmonary hypertension by using 2D STE.Patients and methodsA total of 40 patients with SSc (mean age 48.5 ± 11.4 years, 28 female) and 40 healthy volunteers (mean age 45.9 ± 7.6 years, 21 female) were included in the study. All subjects underwent transthoracic echocardiography for evaluation of RV and RA functions with 2D STE.ResultsAlthough left ventricular systolic and diastolic functions, systolic pulmonary artery pressure (PAP), and RA measurements were similar in both groups, tricuspid annular plane systolic excursion (TAPSE) and maximum systolic myocardial velocity (S’) were decreased in SSc patients. The RV free wall global longitudinal strain (GLS) of SSc patients was lower than the controls (− 18.5 ± 4.9 % vs. − 21.8 ± 2.4 %, p < 0.001) and the RA reservoir and conduit functions were also decreased in SSc patients compared with controls (34.4 ± 9.9 % vs. 39.7 ± 11.2 %, p = 0.027 and 15.0 ± 5.7 % vs. 18.7 ± 6.4 %, p = 0.009, respectively). Disease duration was inversely correlated with RVGLS and TAPSE (r: − 0.416, p = 0.018 and r: − 0.383, p = 0.031, respectively).ConclusionThe use of 2D STE can be helpful in the detection of impairment in RV and RA functions in SSc patients with normal PAP.ZusammenfassungHintergrundDie systemische Sklerose (SSc) ist eine systemische Bindegewebserkrankung, und die Herzbeteiligung stellt eine der Haupttodesursachen dar. Eine rechtsventrikuläre (RV) systolische Funktionseinschränkung ist ein Befund, der bei SSc-Patienten für eine schlechte Prognose steht. Die Untersuchung der RV-Funktion ist aufgrund der Halbmondform und ausgedehnter Trabekulierungen des RV schwierig. Die zweidimensionale (2-D-)Speckle-Tracking-Echokardiographie (STE) ist eine winkelunabhänigige quantitative Untersuchungstechnik für die Myokardfunktion. Ziel dieser Studie war es, die Funktion des RV und des rechten Vorhofs (RA) bei SSc-Patienten ohne pulmonale Hypertonie mittels 2-D-STE zu ermitteln.Patienten und MethodenIn die Studie wurden 40 Patienten mit SSc (Durchschnittsalter: 48,5 ± 11,4 Jahre, 28 w) und 40 gesunde Kontrollen (Durchschnittsalter: 45,9 ± 7,6 Jahre, 21 w) aufgenommen. Bei allen Teilnehmern wurden die RV- und RA-Funktion mittels transthorakaler Echokardiographie in Kombination mit 2-D-STE untersucht.ErgebnisseDie linksventrikuläre systolische und diastolische Funktion, der systolische Pulmonalarteriendruck (PAP) und die RA-Messungen waren in beiden Gruppen zwar ähnlich, aber die systolische Exkursion auf der Ebene des Trikuspidalrings (TAPSE) und die maximale systolische Myokardgeschwindigkeit (S‘) waren bei SSc-Patienten vermindert. Der globale longitudinale Strain (GLS) der freien RV-Wand war bei SSc-Patienten geringer als bei den Kontrollen (− 18,5 ± 4,9 % vs. − 21,8 ± 2,4 %; p < 0,001) und auch die Reservoir- und Conduitfunktion war bei den SSc-Patienten gegenüber den Kontrollen vermindert (34,4 ± 9,9 % vs. 39,7 ± 11,2 %; p = 0,027 bzw. 15,0 ± 5,7 % vs. 18,7 ± 6,4 %; p = 0,009). Die Krankheitsdauer stand in inverser Korrelation mit dem RV-GLS und TAPSE (r − 0,416; p = 0,018 bzw. r − 0,383; p = 0,031).SchlussfolgerungDer Einsatz der 2-D-STE könnte zur Erkennung einer Einschränkung der RV- und RA-Funktion bei SSc-Patienten mit normalem PAP von Nutzen sein.

Assessment of the New 2012 EULAR/ACR Clinical Classification Criteria for Polymyalgia Rheumatica: A Prospective Multicenter Study

Objective. To assess the performance of the new 2012 provisional European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) polymyalgia rheumatica (PMR) clinical classification criteria in discriminating PMR from other mimicking conditions compared with the previous 5 diagnostic criteria in a multicenter prospective study. Methods. Patients older than 50 years, presenting with new-onset bilateral shoulder pain with elevated acute-phase reactants (APR), were assessed for the fulfillment of the new and old classification/diagnostic criteria sets for PMR. At the end of the 1-year followup, 133 patients were diagnosed with PMR (expert opinion) and 142 with non-PMR conditions [69 rheumatoid arthritis (RA)]. Discriminating capacity, sensitivity, and specificity of the criteria sets were estimated. Results. Discriminating capacity of the new clinical criteria for PMR from non-PMR conditions and RA as estimated by area under the curve (AUC) were good with AUC of 0.736 and 0.781, respectively. The new criteria had a sensitivity of 89.5% and a specificity of 57.7% when tested against all non-PMR cases. When tested against all RA, seropositive RA, seronegative RA, and non-RA control patients, specificity changed to 66.7%, 100%, 20.7%, and 49.3%, respectively. Except for the Bird criteria, the 4 previous criteria had lower sensitivity and higher specificity (ranging from 83%–93%) compared with the new clinical criteria in discriminating PMR from all other controls. Conclusion. The new 2012 EULAR/ACR clinical classification criteria for PMR is highly sensitive; however, its ability to discriminate PMR from other inflammatory/noninflammatory shoulder conditions, especially from seronegative RA, is not adequate. Imaging and other modifications such as cutoff values for APR might increase the specificity of the criteria.

The 2013 ACC/AHA 10-year atherosclerotic cardiovascular disease risk index is better than SCORE and QRisk II in rheumatoid arthritis: is it enough?

OBJECTIVE To determine the ability of the new American College of Cardiology and American Heart Association (ACC/AHA) 10-year atherosclerotic cardiovascular disease (ASCVD) risk algorithm in detecting high cardiovascular (CV) risk, RA patients identified by carotid ultrasonography (US) were compared with Systematic Coronary Risk Evaluation (SCORE) and QRisk II algorithms. METHODS SCORE, QRisk II, 2013 ACC/AHA 10-year ASCVD risk and EULAR recommended modified versions were calculated in 216 RA patients. In sonographic evaluation, carotid intima-media thickness >0.90 mm and/or carotid plaques were used as the gold standard test for subclinical atherosclerosis and high CV risk (US+). RESULTS Eleven (5.1%), 15 (6.9%) and 44 (20.4%) patients were defined as having high CV risk according to SCORE, QRisk II and ACC/AHA 10-year ASCVD risk, respectively. Fifty-two (24.1%) patients were US + and of those, 8 (15.4%), 7 (13.5%) and 23 (44.2%) patients were classified as high CV risk according to SCORE, QRisk II and ACC/AHA 10-year ASCVD risk, respectively. The ACC/AHA 10-year ASCVD risk index better identified US + patients than SCORE and QRisk II (P < 0.0001). With EULAR modification, reclassification from moderate to high risk occurred only in two, five and seven patients according to SCORE, QRisk II and ACC/AHA 10-year ASCVD risk, respectively. CONCLUSION The 2013 ACC/AHA 10-year ASCVD risk estimator was better than the SCORE and QRisk II indices in RA, but still failed to identify 55% of high risk patients. Furthermore adjustment of threshold and EULAR modification did not work well.

Right ventricular and atrial functions in systemic sclerosis patients without pulmonary hypertension. Speckle-tracking echocardiographic study.

BackgroundSystemic sclerosis (SSc) is a systemic connective tissue disease and cardiac involvement is one of the most important causes of death. Right ventricular (RV) systolic dysfunction is a poor prognostic finding in SSc patients. Assessment of RV function has some difficulties because of its crescent shape and extensive trabeculations. Two-dimensional (2D) speckle-tracking echocardiography (STE) is an angle-independent quantitative technique to evaluate myocardial function. The aim of this study was to assess the RV and right atrial (RA) functions of SSc patients without pulmonary hypertension by using 2D STE.Patients and methodsA total of 40 patients with SSc (mean age 48.5 ± 11.4 years, 28 female) and 40 healthy volunteers (mean age 45.9 ± 7.6 years, 21 female) were included in the study. All subjects underwent transthoracic echocardiography for evaluation of RV and RA functions with 2D STE.ResultsAlthough left ventricular systolic and diastolic functions, systolic pulmonary artery pressure (PAP), and RA measurements were similar in both groups, tricuspid annular plane systolic excursion (TAPSE) and maximum systolic myocardial velocity (S’) were decreased in SSc patients. The RV free wall global longitudinal strain (GLS) of SSc patients was lower than the controls (− 18.5 ± 4.9 % vs. − 21.8 ± 2.4 %, p < 0.001) and the RA reservoir and conduit functions were also decreased in SSc patients compared with controls (34.4 ± 9.9 % vs. 39.7 ± 11.2 %, p = 0.027 and 15.0 ± 5.7 % vs. 18.7 ± 6.4 %, p = 0.009, respectively). Disease duration was inversely correlated with RVGLS and TAPSE (r: − 0.416, p = 0.018 and r: − 0.383, p = 0.031, respectively).ConclusionThe use of 2D STE can be helpful in the detection of impairment in RV and RA functions in SSc patients with normal PAP.ZusammenfassungHintergrundDie systemische Sklerose (SSc) ist eine systemische Bindegewebserkrankung, und die Herzbeteiligung stellt eine der Haupttodesursachen dar. Eine rechtsventrikuläre (RV) systolische Funktionseinschränkung ist ein Befund, der bei SSc-Patienten für eine schlechte Prognose steht. Die Untersuchung der RV-Funktion ist aufgrund der Halbmondform und ausgedehnter Trabekulierungen des RV schwierig. Die zweidimensionale (2-D-)Speckle-Tracking-Echokardiographie (STE) ist eine winkelunabhänigige quantitative Untersuchungstechnik für die Myokardfunktion. Ziel dieser Studie war es, die Funktion des RV und des rechten Vorhofs (RA) bei SSc-Patienten ohne pulmonale Hypertonie mittels 2-D-STE zu ermitteln.Patienten und MethodenIn die Studie wurden 40 Patienten mit SSc (Durchschnittsalter: 48,5 ± 11,4 Jahre, 28 w) und 40 gesunde Kontrollen (Durchschnittsalter: 45,9 ± 7,6 Jahre, 21 w) aufgenommen. Bei allen Teilnehmern wurden die RV- und RA-Funktion mittels transthorakaler Echokardiographie in Kombination mit 2-D-STE untersucht.ErgebnisseDie linksventrikuläre systolische und diastolische Funktion, der systolische Pulmonalarteriendruck (PAP) und die RA-Messungen waren in beiden Gruppen zwar ähnlich, aber die systolische Exkursion auf der Ebene des Trikuspidalrings (TAPSE) und die maximale systolische Myokardgeschwindigkeit (S‘) waren bei SSc-Patienten vermindert. Der globale longitudinale Strain (GLS) der freien RV-Wand war bei SSc-Patienten geringer als bei den Kontrollen (− 18,5 ± 4,9 % vs. − 21,8 ± 2,4 %; p < 0,001) und auch die Reservoir- und Conduitfunktion war bei den SSc-Patienten gegenüber den Kontrollen vermindert (34,4 ± 9,9 % vs. 39,7 ± 11,2 %; p = 0,027 bzw. 15,0 ± 5,7 % vs. 18,7 ± 6,4 %; p = 0,009). Die Krankheitsdauer stand in inverser Korrelation mit dem RV-GLS und TAPSE (r − 0,416; p = 0,018 bzw. r − 0,383; p = 0,031).SchlussfolgerungDer Einsatz der 2-D-STE könnte zur Erkennung einer Einschränkung der RV- und RA-Funktion bei SSc-Patienten mit normalem PAP von Nutzen sein.

Risk factors for malignancy in systemic sclerosis patients.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with multisystem involvement. An increased incidence of cancer in SSc patients compared with the general population has been reported in several reports. Our aims in this study were to determine the most common malignancies and to investigate the possible risk factors for the development of malignancy in patients with SSc. Three hundred forty SSc patients from 13 centers were included to the study. Data of the patients were obtained by evaluating their medical records retrospectively. A total of 340 patients with SSc were evaluated. Twenty-five of the patients had 19 different types of malignancy. Bladder cancer was the most common type of cancer with four patients and was followed by breast cancer with three patients, and cervix cancer and ovarian cancer with two patients each. Other types of cancers such as squamous cell skin cancer, adenocancer with an unknown origin, multiple myeloma, chronic myeloid leukemia, papillary thyroid cancer, larynx cancer, non-small cell lung cancer, follicular type non-Hodgkin lymphoma (NHL), endometrium cancer, colon cancer, uterus cancer, neuroendocrine tumor, glioblastoma multiforme, and soft tissue sarcoma were diagnosed in one patient each. The only cancer type that showed an association with cyclophosphamide dose was bladder carcinoma. Other malignancies did not show a correlation with age, sex, smoking, type and duration of the disease, autoantibodies, organ involvement, and dose and duration of cyclophosphamide therapy. Cancer may develop in any organ in patients with SSc. Continuous screening of the patients during a follow-up period is necessary for the early detection of the tumor development.

Evaluation of left atrial volume and function in systemic sclerosis patients using speckle tracking and real-time three-dimensional echocardiography

Objective: The aim of the present study was to evaluate left atrial (LA) volume and functions using real-time three-dimensional echocardiography (RT3DE) and speckle tracking in systemic sclerosis (SSc) patients. Methods: The study was designed as a cross-sectional observational study. We studied 41 consecutive SSc patients (38 females, mean age: 49.5±11.6 years) and 38 healthy controls (35 females, mean age: 48.5±10.8 years). Patients with evidence or history of cardiovascular disease and patients with risk factors as hypertension, diabetes and chronic renal failure were excluded from the study. All study subjects underwent standard echocardiography; LA speckle tracking and RT3DE was performed to assess LA volume and phasic functions. Differences between numeric variables were tested using the independent sample Student’s t-test or Mann-Whitney U test, where appropriate. Results: There were no significant differences between SSC patients and controls regarding left ventricular (LV) systolic functions and two-dimensional (2-D) atrial diameters. Presence of LV diastolic dysfunction (LVDD) was evaluated and graded according to recommendations of the American Society of Echocardiography. Accordingly, LVDD was observed to be significantly more frequent in SSc patients; 16 SSc patients (39%) and 5 controls (12.8%) were observed to have LVDD (p=0.007). With regard to results obtained from RT3DE, LA maximum, minimum, and before atrial contraction volumes were significantly higher (40.5±14.6 vs. 32.6±8.9, 15.5±8.4 vs. 9.9±3.5 and 28.7±11.7 vs. 21.4±7.0 mL respectively, p<0.05 for all), whereas LA active emptying fraction, LA total emptying fraction, LA expansion index, and passive emptying fraction values were significantly (47.1±12.0 vs. 52.9±10.1%, 62.8±10.5 vs. 69.5±6.7%, 187.5±76.0 vs. 246.6±96.0, 29.6±9.3 vs. 34.4±11.0% respectively, p<0.05 for all) in SSc patients than in controls. In addition, regarding results obtained from speckle tracking echocardiography, atrial peak-systolic longitudinal strain (e), early negative strain rate (SR), late negative SR, and peak positive SR values were observed to be significantly lower in SSc patients. Conclusion: LA volumes were significantly increased, and LA reservoir, conduit, and contractile functions were significantly impaired in SSc patients compared with controls. LA volume and functional analyses with RT3DE and speckle tracking may facilitate the recognition of subtle LA dysfunction in SSc patients.

Subclinical Atherosclerosis in Systemic Sclerosis: Not Less Frequent Than Rheumatoid Arthritis and Not Detected With Cardiovascular Risk Indices.

To determine the frequency of subclinical atherosclerosis in patients with systemic sclerosis (SSc; scleroderma) compared to healthy subjects (HS) and rheumatoid arthritis (RA) patients and to determine the ability of cardiovascular (CV) risk indices in detecting SSc patients with subclinical atherosclerosis.

Activation of the JAK/STAT pathway in Behcet's disease (Genes and Immunity (2015) 16 DOI: 170-175; doi:10.1038/gene.2014.64)

Correction to: Genes and Immunity (2014) 0, 000–000; doi:10.1038/gene.2014.64; published online 20 November 2014 Since the online publication of this paper, the authors have noted the following errors. The author JD Wren was incorrectly linked to affiliation 1 instead of affiliation 2. The correct details are shown above.

Regional myocardial dysfunction assessed by two-dimensional speckle tracking echocardiography in systemic sclerosis patients with fragmented QRS complexes

BACKGROUND The aim of the study was to explore the relation between regional myocardial dysfunction and fragmented QRS (fQRS) complexes in systemic sclerosis (SSc). METHODS Fifty-three SSc patients and 26 controls were included. All subjects underwent speckle tracking echocardiography for evaluation of left ventricular (LV) function and ECG to check for fQRS complexes. RESULTS SSc patients had significantly lower LV global longitudinal, radial and circumferential strain and twist compared to controls. Thirteen SSc patients had fQRS (DII, DIII, aVF leads in eleven patients and V1 to V5 leads in two patients) and they had significantly lower global longitudinal and circumferencial strain compared to SSc patients with normal QRS. The SSc patients with fQRS in DII, DIII, and aVF leads had impaired longitudinal strain and delay in time to peak longitudinal strain in inferior LV segments compared to those with normal QRS. CONCLUSION fQRS is associated with lower strain measures in SSc patients indicating impairment in LV function.