Evaluation of cardiac autonomic functions in patients with systemic lupus erythematosus.

BACKGROUND: Cardiovascular involvement is one of the leading causes of death among patients with systemic lupus erythematosus (SLE). In this study, we aimed to investigate cardiac autonomic functions in SLE patients. METHODS: We enrolled 36 patients (25 female; mean age 34.2 ± 10.2 years) with SLE and 32 healthy subjects (23 female; mean age 35.0 ± 10.3 years). All participants underwent 24-h Holter recording. Heart rate recovery (HRR) indices were calculated by subtracting first, second, and third-minute heart rates from maximal heart rate. All patients underwent heart rate variability (HRV), heart rate turbulence (HRT) and QT dispersion analysis. The mean SLE duration was 8.4 ± 4.0 years. RESULTS: According to the baseline demographic characteristics, both groups were similar with regard to age, gender, body mass index and left ventricular ejection fraction. Mean HRR1 (32.6 ± 10.9 vs. 42.5 ± 6.5, p = 0.038), HRR2 (51.0 ± 16.9 vs. 61.0 ± 10.8, p = 0.01) and HRR3 (52.8 ± 17.5 vs. 65.8 ± 9.8, p < 0.001) values were significantly higher in control group. When HRV was considered, SDNN, SDANN, RMSSD, PNN50 and high frequency (HF) component were significantly decreased in patients with SLE compared with healthy controls, but low frequency (LF) component and LF/HF were significantly higher in SLE patients. In addition, HRT onset and HRT slope values were significantly less negative in SLE patients. QT dispersion was significantly greater in SLE patients than healthy subjects (81.3 ± 15.8 vs. 53.2 ± 13.1, p < 0.001). CONCLUSION: Our study results suggest that cardiac autonomic functions are impaired in SLE patients despite the absence of overt cardiac involvement and symptoms. Further studies are needed to elucidate the prognostic significance and clinical implications of impaired autonomic functions in patients with SLE.

Infliximab, a TNF-α antagonist treatment in patients with ankylosing spondylitis: the impact on depression, anxiety and quality of life level.

The objective of this study was to assess the effect of infliximab on depression, anxiety and quality of life in patients with active ankylosing spondylitis (AS). In this 6-week longitudinal study, 16 patients with AS were assessed. Active disease as defined by BASDAI ≥4.0 was sought for inclusion. Infliximab was administered 5 mg/kg at 0, 2 weeks and 6 weeks. Collected data included age, sex and date of onset of rheumatologic disease. Activity of disease was measured using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Biological activity was evaluated with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). ESR and CRP were assessed at baseline and day 42. The Hospital Anxiety and Depression scale (HADS), Beck Depression Inventory (BDI) and 36-item Short Form Health Survey (SF-36) were used to evaluate anxiety, depression and quality of life. BASDAI, SF-36, HADS and BDE were assessed prior to the initial infliximab dose and at 2nd, 14th and 42nd day. Seven (43.8%) AS patients had depression scores above the cut off value for both the HADS depression (HADS-D) and BDI and 4 (25 %) had high HADS anxiety scores at baseline. Significant time effect for BDI and HADS-D scores were observed. Although significantly lower BDI scores were found after first, second and third infusions of infliximab, compared to initial score, the significant decrease in HADS-D appeared after second and third infusions. A significant time effect for HADS-anxiety scores were found as well. All of the subscales of SF-36 improved significantly during the course, with an exception of role emotional, for which the difference approached to the significance. The change in BASDAI scores and CRP and ESR, in the treatment process, were not correlated with the change in depression and anxiety scores. Infliximab which is an anti-TNF-α drug, may be effective in the treatment of depression accompanying AS. Possible implications for the treatment of major depressive disorder were discussed, as well.

Plasma and platelet serotonin levels in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF) is the most common auto-inflammatory syndrome with exaggerated acute phase and inflammatory response. After revealing the MEFV gene mutation with the finally disturbed end product pyrin, some of the mechanisms were explained. However it is still unknown what triggers or ends these periodical attacks. Moreover, the treatment of up to 30% of the patients, that are resistant to colchicine is still a problem. In this study we investigated the role of serotonin in colchicine-resistant FMF patients. METHODS: Twenty-four FMF patients (male/female: 15/9) and 32 age- and sex-matched healthy controls (male/female: 17/15) were included into the study. Patients were subdivided into two groups. Thirteen had FMF attacks despite regular colchicine (colchicine-resistant group), other 11 had disease under control with colchicine for at least 6-months. Sampling was done both during the attack and ten days after its cessation. Plasma and platelet serotonin levels and acute phase reactants were studied in patients and controls. RESULTS: Colchicine-resistant patients had plasma serotonin (5-HT) levels of 7.85 +/- 1.0 nmol/l during acute attacks which significantly reduced to the levels of 6.3 +/- 0.6 nmol/l (p < 0.001), after 10 days of acute attacks and these levels were significantly lower than those of attack-free patients' and controls' (10.7 +/- 0.2 nmol/l and 10.1 +/- 0.3 nmol/l, respectively). Platelet 5-HT level was 6.4 +/- 0.3 nmol/10(9) platelets during acute attack, and this level was increased to 9.8 +/- 0.5 nmol/10(9) platelets on the 2(nd) sampling, 10 days after the cessation of the acute attack (p < 0.001). They were both significantly higher than those of attack-free FMF patients (5.9 +/- 0.1 nmol/10(9) platelets) and healthy controls (5.7 +/- 0.3 nmol/10(9) platelets). There was a negative correlation between plasma and platelet 5-HT levels (r=-0.77, p < 0.001). CONCLUSION: Changes in plasma and platelet 5-HT levels may be related to the disturbances in 5-HT transport mechanisms or may also be attributed to the potential role of serotonin in the inflammatory cascade. Last but not least, serotonin may have a role in the pathogenesis of FMF.

Successful treatment of myelodysplastic syndrome-induced pyoderma gangrenosum.

We report successful treatment of a refractory myelodysplastic syndrome-associated pyoderma gangrenosum with the combination of thalidomide and interferon-alpha2a in a single patient. A non-healing wound developed on a 40-year-old woman's left thumb after minor trauma. Massive ulcerovegetative lesions developed after reconstruction surgery. Histopathological examination of the bone marrow and cytogenetic studies revealed an atypical myeloproliferative/myelodysplastic syndrome. The skin lesions resolved dramatically after two months of thalidomide and interferon-alpha2a combination therapy and the haematological status improved.

Circulating thrombomodulin levels in familial Mediterranean fever.

Increments in circulating thrombomodulin levels reflect endothelial cell injury. Thrombomodulin can also be synthesized by several inflammatory cells including monocytes, neutrophils, and thrombomodulin itself can modulate the inflammatory response. In this study, we assessed circulating thrombomodulin concentrations in patients with familial Mediterranean fever (FMF). Twenty-five patients with FMF (F/M: 14/11) (mean age: 31.1 +/- 9.7 years) and 25 healthy controls (F/M: 13/12) (mean age: 34.6 +/- 7.0 years) were involved in the study. Thrombomodulin levels were measured by commercially available enzyme-linked immunosorbant assay (ELISA) (Immunoassay of thrombomodulin Diagnostica Stago, Asnieres-Sur-Seine, France). Twenty of the patients were in attack-free period and the remaining five had been during acute FMF attacks. Thrombomodulin levels were higher in the study group (20.9 +/- 12.1 ng/ml) than healthy controls (14.1 +/- 8.4 ng/ml) (p < 0.05). Circulating thrombomodulin levels were also higher in attack-free FMF patients (22.4 +/- 12.9 ng/ml) than controls. This study disclosed for the first time significantly higher increments in the circulating levels of thrombomodulin in FMF. This observation could be a consequence of injured endothelium and/or activated inflammatory cells.

Extra-articular manifestations of rheumatoid arthritis: results of a university hospital of 526 patients in Turkey.

OBJECTIVE: Presence of extra-articular manifestations (EAM) in rheumatoid arthritis (RA) is associated with more severe disease and increased mortality. Prevalence of EAM may vary in different geographic areas and in different ethnic populations. In this study we investigated the frequency of EAM in 526 RA patients from a single university hospital in Turkey. METHODS: The hospital records of patients who had been diagnosed as RA in Hacettepe University Department of Rheumatology between the years 1988 and 2003 were retrospectively evaluated. There were 73 males and 453 females, and mean age of the patients was 48.0 +/- 12.3 years. The mean follow-up period was 4.8 +/- 4.1 years. Three hundred and fifty-nine patients were rheumatoid factor (RF) positive (68.3%). RESULTS: The overall frequency of EAM was 38.4% (202 patients). The most common EAM was rheumatoid nodules (18.1%). Sicca symptoms, pulmonary findings, Raynaud's phenomenon, livedo reticularis, carpal tunnel syndrome, vasculitis, amyloidosis, and Felty syndrome were present in 11.4%, 4.8%, 3%, 4.8%, 2.8%, 1.3%, 1.1%, and 0.3% of the patients, respectively. Overall EAM and rheumatoid nodules were significantly more common in RF positive patients than RF negative patients. The frequency of rheumatoid nodules was significantly higher in males than in females. CONCLUSION: The prevalence of EAM in Turkey is higher than East Asia and Africa, and lower than UK and North America. Excluding secondary Sjögren's syndrome, our results are similar to other Mediterranean populations like Italy.

Serum interleukin 17 and interleukin 18 levels in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF) attacks are characterized by serosal inflammation rich in PMNL leukocytes and activation of a definite cytokine network. Moreover, there is sustained inflammation in attack-free FMF patients. Interleukin (IL)-17 and IL-18 are recently described proinflammatory cytokines, which can modulate certain neutrophil functions. In this study we measured serum levels of IL-17 and IL-18 in FMF patients. METHODS: The study groups comprised of 18 FMF patients in attack-free period (mean age: 30.2 +/- 9.5 years; male/female: 10/8), and 18 patients with an acute FMF attack (mean age: 25.4 +/- 4.9 years; male/female: 10/8). Twenty age-matched healthy subjects were included as a control group (male/female: 10/10). Levels of IL-17 and IL-18 were determined by commercial ELISA kits (Biosource International, USA). RESULTS: Serum IL-17 levels were 42.8 +/- 3.7, 42.7 +/- 3.2, and 39.9 +/- 2.3 pg/mL for FMF patients in attack-free period, FMF patients with acute attack, and healthy controls, respectively. Serum IL-18 levels were 878.8 +/- 315.0, 854.2 +/- 261.4, and 314.6 +/- 80.8 pg/mL for FMF patients in an attack-free period, FMF patients with acute attack, and healthy controls, respectively. Levels of both IL-17 and IL-18 were significantly higher in FMF patients with and without acute attack compared to control group (p < 0.05). Concentrations of those cytokines were comparable in FMF patients with acute attack and in attack-free period (p > 0.05). CONCLUSION: Our data suggest that IL-17 and IL-18 contribute to the cytokine network in the inflammatory cascade of FMF. However, their roles for the initiation of FMF attacks remain to be established.

The efficacy of continuous interferon alpha administration as an adjunctive agent to colchicine-resistant familial Mediterranean fever patients.

OBJECTIVE: About 10-20% of familial Mediterranean fever (FMF) patients are resistant to regular colchicine treatment and have painful recurrent attacks due to polyserositis. In clinical practice there is no alternative drug for such patients. In a previous pilot study on a small number of colchicine-resistant patients, interferon-alpha (IFN-alpha) was administered when painful attacks were about to occur. METHODS: In this study we gave IFN-alpha continuously to 8 colchicine-resistant FMF patients in a schedule while the colchicine therapy had been continued. All those patients were complicated with vasculitis or arthritis or together during the FMF course. Those complications were treated with the other immunosuppressive drugs. While they were under intense immunosuppressive therapy, the abdominal and the other serosal attacks remained to continue. RESULTS: After the administration of IFN-alpha therapy only one out of eight patients had abdominal painful attacks in twice, and one patient had arthritis in knees and ankles, the others responded well. Observed side effects were generally mild and acceptable. CONCLUSION: Continuous IFN administration in addition to the regular colchicine treatment may be useful for the colchicine-resistant attacks in FMF patients.

The contribution of underlying systemic rheumatic diseases to the mortality in patients admitted for intensive care: a matched cohort study.

OBJECTIVE: The aim of this study was to determine the outcome of patients with systemic rheumatic diseases admitted to our medical-intensive care unit (ICU) in comparison to the outcome of patients with non-rheumatic diseases in the same ICU. METHODS: The hospital files of 50 patients with systemic rheumatic diseases who were treated in the medical-ICU of Hacettepe University Hospital, Ankara between 1995 and 2001 were retrospectively evaluated. 50 patients without any underlying systemic rheumatic diseases admitted to the medical-ICU in the same time period and matched for age, gender and acute physiology and chronic health evaluation scores were included in the control group. ICU outcome was compared between the two groups. RESULTS: The acute physiology score of the study group was lower than that of the control group (13.4 +/- 5.7 [SD] vs. 17.3 +/- 7.2, p = 0.04). Moreover, the study group received more immunosuppressive treatment but less invasive procedures (i.e. mechanical ventilation and central venous catheterization). Mortality rates (56% vs. 54%, respectively, p = 0.5), lengths of stay in the ICU and in the hospital, the infection rates were similar between the rheumatic disease group and the control group. CONCLUSION: The presence of a systemic rheumatic disease seems to negatively affect the outcome in patients under intensive care.

The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis.

Pharmacological treatment of diffuse systemic sclerosis (SSc) directed at the tissue fibrosis has generally been ineffective. Many immunosuppressive drugs have been tried as therapy for SSc, regardless of the disease subtype and/or stage. The aim of this study was to show the efficacy and the toxicity of oral cyclophosphamide and prednisolone therapy on the prevention of fibrosis-based tissue damage in the early stages of the diffuse SSc. Twenty-seven patients with early diffuse SSc were treated with oral cyclophosphamide (1-2 mg/kg/day) plus oral prednisolone (40 mg/every other day) between the years 1995 and 1998. The results regarding the efficacy and toxicity of cyclophosphamide were compared with those of 22 early SSc patients who had been treated with oral D-penicillamine between 1992 and 1995. All the patients were evaluated using clinical and laboratory parameters every 6 months for 2 years. There was a significant improvement on the skin score, maximal oral opening, flexion index, predicted forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) in the cyclophosphamide group. The decrease in skin score in the cyclophosphamide group started earlier than in the D-penicillamine group. No life-threatening or irreversible adverse reaction was observed. This open study supports the use of oral cyclophosphamide plus prednisolone therapy to prevent fibrosis and its complications in the early stages of diffuse SSc.

Frequency of lymphadenopathy in rheumatoid arthritis and systemic lupus erythematosus.

This study aimed to assess the frequency of all palpable lymph nodes during active disease and remission in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Hospital records of 100 SLE patients, 100 RA patients, 100 spondyloarthropathy patients, and 150 osteoarthritis patients, treated in our rheumatology department, were evaluated retrospectively. Overall frequencies of enlarged lymph nodes in patients with active RA and SLE were 82% and 69%, respectively. Enlarged lymph nodes associated with RA were mostly located in the axillary region, and in SLE the nodes were smaller and lymphadenopathy was more generalized compared with RA. Palpable lymph nodes disappeared in the majority of patients during remission. Lymphadenopathy was significantly less frequent in patients treated with steroids before admission. Lymph node enlargement is an important physical finding associated with RA and SLE disease activity. Atypical locations and unusually large lymph nodes should raise clinical suspicion of another underlying disease.

Bloodstream thrombopoietin in rheumatoid arthritis with thrombocytosis.

Thrombopoietin (TPO) is the major regulator of growth and differentiation of megakaryocytes. Recent studies have shown that TPO may also act as an acute-phase reactant, and it has been suggested as a component of inflammatory reactions. In this study our objective was to investigate serum TPO levels in patients with rheumatoid arthritis, a complex chronic inflammatory disorder not uncommonly associated with thrombocytosis. Bloodstream TPO concentrations were assessed in 13 RA patients with platelet counts between 450 and 650 x 10(9)/l, 10 RA patients with platelet counts >650 x 10(9)/l, 15 RA patients with normal platelet counts and 12 healthy controls. RA patients with normal platelet counts had TPO levels comparable with healthy controls. TPO concentrations in patients with mild thrombocytosis were significantly elevated, whereas patients with markedly increased thrombocyte counts had prominently decreased TPO levels. These results indicate that TPO seems to be associated with reactive thrombocytosis in RA patients with active disease. In patients with extremely increased thrombocytosis serum TPO levels might be regulated by increased platelet mass via receptor-mediated uptake and metabolism.

Echocardiographic evidence of cardiac involvement in ankylosing spondylitis.

Aortic insufficiency, myocardial fibrosis and conduction disturbances are known complications of ankylosing spondylitis (AS). However, few studies have assessed left ventricular diastolic function and no data are available about P-wave analysis. In this study 88 AS patients and 31 healthy volunteers underwent clinical examination, electrocardiography, echocardiography and signal-averaged P-wave analysis for the evaluation of asymptomatic cardiac involvement. The aortic root in AS patients was larger and this was correlated with the duration of the disease. Five of 88 AS patients (5.7%) had evidence of mitral valve prolapse, six (6.8%) had thick and redundant mitral valves without prolapse, five (5.7%) had mild mitral regurgitation, two had moderate (2.3%) and two had mild (2.3%) aortic regurgitation. Examination of diastolic function revealed a lower peak of E-wave velocity (E) and E/A ratio, a higher peak of A-wave velocity (A) and acceleration rate of the A wave, a longer deceleration time of E-wave velocity and isovolumic relaxation time in the AS group compared to controls. Mean filtered P-wave duration (PWD) in AS was similar to that of controls. However, PWD in AS patients was positively correlated with left atrial dimension and acceleration rate of the A wave and negatively correlated with E and E/A ratio. In conclusion, cardiac involvement may be seen in AS patients in the absence of clinical manifestations. Echocardiographic examination of diastolic function can be used in this asymptomatic period. Further studies are needed to clarify the prognostic significance of diastolic abnormalities and the value of P-wave analysis in cardiac evaluation of these patients.

Changes in the concentration and distribution of tissue factor pathway inhibitor in Behçet's disease and systemic lupus erythematosus: effect on the prethrombotic state.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is an anticoagulant which modulates the tissue factor (TF) dependent pathway, acting on the factor VIIa/TF complex, factor Xa, and thrombin. Although most TFPI is found in association with plasma lipoproteins and platelets, the functional pool is bound to vascular endothelium and is released into the circulation on stimulation with heparin or low molecular weight heparin (LMWH). OBJECTIVE: To assess the vascular endothelial TFPI pool in patients with Behçet's disease (BD) or systemic lupus erythematosus (SLE). METHODS: Plasma TFPI concentrations were determined before, and 20 and 60 minutes after subcutaneous LMWH injection in 15 newly diagnosed patients with BD and 12 with SLE, and in 12 healthy controls. RESULTS: Baseline median TFPI was 149.5 ng/ml in healthy subjects, and the percentage change in TFPI at 20 minutes (((value at 20th min - baseline value)/baseline value) x 100) was 575.2. TFPI concentrations in patients with BD were initially normal at baseline (136.0 ng/ml), but the percentage change (44.7) was significantly lower than in the patients with SLE and the controls. Baseline TFPI concentrations in patients with SLE (83.0 ng/ml) were lower than in the control group, but the TFPI response to stimulation with LMWH reached a level (626.4%) comparable to that of the controls. CONCLUSION: Depletion of the functional endothelial pool in BD and low circulating concentrations of TFPI despite an intact pool in SLE may be important in the pathogenesis of thrombosis in these vasculitic syndromes.

Plasma fibronectin- and thrombospondin-adhesive molecules during acute attacks and attack-free periods of familial Mediterranean fever.

We assessed plasma concentrations of fibronectin (FN) and thrombospondin (TSP) during acute attacks and attack-free periods of patients with familial Mediterranean fever (FMF). Seven female and three male FMF patients (mean age 34+/-7 years) were enrolled in the study. Plasma samples were obtained during acute FMF attacks and after 3 months of freedom from attacks. Erythrocyte sedimentation rate, C-reactive protein, and white blood cell count were evaluated concurrently. Plasma levels of FN and TSP were assayed by enzyme-linked immunosorbent assay (ELISA). Both FN and TSP concentrations were found to increase during acute attacks. Levels of adhesive molecules decreased during attack-free periods (P < 0.05). Significant correlations were found between FN and TSP levels and the concentrations of acute-phase response indicators (P< 0.05). This study disclosed for the first time significantly higher increments in the plasma levels of FN and TSP during acute FMF attacks than in attack-free periods. Therefore, the two matrix glycoproteins may play precipitating and/or regulatory roles in the inflammatory processes of these attacks.

No evidence of cardiac autonomic involvement in ankylosing spondylitis, as assessed by heart rate variability.

The aim of this study was to investigate the involvement of autonomic nervous system (ANS) function by using power spectral analysis of heart rate variability (HRV) method in patients with ankylosing spondylitis (AS). The study included 94 AS patients all fulfilling the New York criteria for AS, and 49 healthy volunteers. Recordings for HRV were obtained with a PC-based high-resolution electrocardiographic system and analysed using power spectral analysis. The peak around 0.04-0.15 Hz was defined as low-frequency peak (LF) and the other, around 0. 15-0.40 Hz, was defined as high-frequency peak (HF), representing mostly the sympathetic and the parasympathetic components of the ANS, respectively. The following variables were calculated and compared between groups: the LF in absolute and normalised units (LF nU); the HF in absolute and normalised units (HF nU); and LF/HF ratio. The AS group included 47 male and 47 female subjects with a mean age of 33 +/- 11 years (range 16-64). In the control group there were 23 male and 26 female healthy subjects (mean age 33 +/- 8; range 19-60). None of the patients or control subjects had any cardiac or neurological symptoms. Both groups were similar with respect to age and sex characteristics (p > 0.05). The HRV analysis indicated that the peaks of LF, LF nU, HF, HF nU and LF/HF ratio were similar in both groups. Groups also did not differ with respect to heart rate at the time of examination. Our data demonstrated no evidence of ANS involvement as assessed by HRV analysis in AS patients.

Polyarteritis nodosa in patients with Familial Mediterranean Fever (FMF): a concomitant disease or a feature of FMF?

BACKGROUND: Familial Mediterranean Fever (FMF) is caused by mutations in the gene encoding pyrin and is characterized by self-limited, recurrent attacks of fever and serositis. Vasculitis has been increasingly reported in FMF. A study evaluating the prognosis in FMF and polyarteritis nodosa (PAN) patients has not been reported previously. OBJECTIVES: To determine the special characteristics and the prognosis of PAN in FMF patients. METHODS: A questionnaire was used for the present survey. The setting was 7 referral centers from Turkey and Israel. Seventeen patients who were diagnosed with FMF and who developed PAN were included. PAN was diagnosed in those who met the Chapel Hill consensus criteria for microscopic polyarteritis or classic PAN. The clinical features of these 17 patients and the outcomes of their vasculitis were analyzed. RESULTS: The age at diagnosis of PAN in these FMF patients ranged from 3.5 to 37 years. All patients had constitutional symptoms, elevated acute phase reactants, and myalgia at the time PAN was diagnosed. The diagnosis of PAN was confirmed by renal angiography in 8 patients, by renal biopsy in 6 patients, and by muscle and/or nodule biopsies in 6 patients. A number of patients had definite features of both classic PAN and microscopic polyarteritis. CONCLUSIONS: When compared with other PAN patients, those with FMF tended to have a younger age at PAN onset, more frequent perirenal hematomas, and an overall better prognosis. The cases with overlapping features of microscopic and classic PAN pose a problem for the current classification of vasculitis. We suggest that the clinical representation of PAN in FMF patients has certain characteristics and may be a feature of FMF per se.