Interferon-alpha in systemic lupus erythematosus

PURPOSE OF REVIEW: To describe the lines of evidence supporting a significant role for interferon-alpha (IFNalpha) in the pathogenesis of systemic lupus erythematosus (SLE) and to propose potential mechanisms by which IFNalpha contributes to the autoimmunity and immune dysfunction of SLE. RECENT FINDINGS: Long-standing data indicating elevated levels of IFNalpha in the circulation of patients with SLE have recently been supplemented by reports from clinical practice, gene expression data, analysis of patient cells studied ex vivo, and studies of mechanisms of induction of IFNalpha production to provide complementary data strongly supporting a pathogenic role for IFNalpha in SLE. Recombinant IFNalpha, when administered as a therapy to patients with malignancy or hepatitis infection, can induce SLE. IFNalpha-regulated genes are highly expressed in SLE peripheral blood cells compared with cells from control subjects. Functional alterations of SLE mononuclear cells have been attributed to effects of IFNalpha. In addition, immune complexes bearing lupus autoantibodies and RNA or DNA have been shown to induce IFNalpha production. Finally, progress in understanding the role of Toll-like receptors (TLR) in the activation of the innate immune response has suggested potential mechanisms by which adjuvant-like factors act through TLR to induce IFNalpha as well as effective processing of self-antigens, resulting in activation of an adaptive immune response directed against self, as well as cytokine-mediated immune dysfunction. SUMMARY: Substantial evidence supports a significant role for IFNalpha in the pathogenesis of lupus. The IFNalpha pathway represents a promising target for therapeutic intervention in patients with SLE.     

Weight change and mortality among older Mexican Americans

BACKGROUND AND AIMS: Weight changes are predictors of health outcomes in older people. The purpose of this study is to examine the association between 2-year weight change and mortality in older Mexican Americans. METHODS: Seven year prospective cohort study of 1,749 non-institutionalized Mexican American men and women aged 65 and older residing in five Southwestern states. Measures include self-reports of medical conditions (heart attack, stroke, diabetes, hypertension, hip fracture or cancer), functional disability, high depressive symptoms, smoking status, a summary performance score of lower body function, hand grip muscle strength, and body mass index (BMI). Weight change was examined by comparing the baseline weight to the weight two years later to estimate the hazard of death within the following five-year period. RESULTS: Of the 1,749 subjects, 396 (22.6%) lost 5% or more weight, 984 (56.3%) had weight that remained stable, and 369 (21.1%) gained 5% or more weight between baseline and the 2-year follow-up period. Of the ones who lost 5% of weight, 28% died as compared to 19.7% and 15.2% of those whose weight remained stable and those who gained weight after 5 years, respectively. The hazard ratio (HR) of death for the group that lost 5% or more of their weight compared to the reference group (stable weight) was 1.35 (95% CI 1.06-1.70) after controlling for demographic variables, BMI, and waist circumference at baseline and 1.32 (95% CI 1.04-1.67) after controlling for all covariates. The HR of death for the group that gained 5% or more of weight was 0.78 (95% CI 0.58-1.05) after controlling for demographic variables, BMI, and waist circumference at baseline and 0.77 (95% CI 0.57-1.04) after controlling for all covariates. CONCLUSIONS: Weight loss is an independent predictor of mortality among older Mexican Americans, after controlling for relevant risk factors.     

Diverse associations of microalbuminuria with C-reactive protein, interleukin-18 and soluble CD 40 ligand in male essential hypertensive subjects

BACKGROUND: Microalbuminuria (MA) and low-grade inflammation constitute emerging markers of subclinical atherosclerosis. We investigated whether urinary albumin excretion, expressed as the albumin-to-creatinine ratio (ACR), is associated with high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-18, and soluble CD40 ligand (sCD40L), in hypertensive subjects. METHODS: The study population consisted of 108 nondiabetic male patients with newly diagnosed untreated stage I to II essential hypertension (aged 44.6 years, office blood pressure [BP] 148/95 mm Hg). According to ACR values determined as the average of two nonconsecutive overnight spot urine samples, subjects were divided into microalbuminurics (n = 28) (mean ACR = 30 to 300 mg/g) and normoalbuminurics (n = 80) (mean ACR <30 mg/g). RESULTS: Although microalbuminurics as compared to normoalbuminuric hypertensives had greater hs-CRP levels (2.55 +/- 1.18 v 1.45 +/- 0.52 mg/L, P < .0001), independently of confounding factors, these two groups did not differ regarding IL-18 and sCD40L values (P = not significant [NS] for both cases). In the entire population, ACR exhibited a positive correlation with hs-CRP (r = 0.623, P < .0001), whereas there was no association with both IL-18 and sCD40L (P = NS for both cases). When multiple linear regression analysis was performed, it was revealed that age, body mass index, office systolic BP, total cholesterol, and hs-CRP levels were significant independent predictors of the ACR (P < .05). CONCLUSIONS: In essential hypertensive subjects, MA is accompanied by elevated hs-CRP levels, but not by augmented IL-18 and sCD40L concentrations, suggesting activation of different inflammatory pathways in the progression of renal and cardiovascular atherosclerotic disease. The pathophysiologic mechanisms of these associations remain to be further elucidated in future studies.     

Prevalence, awareness, treatment and control of hypertension in Hellas, Greece: the Hypertension Study in General Practice in Hellas (HYPERTENSHELL) national study

BACKGROUND: The Hypertension Study in General Practice in Hellas (Hypertenshell) is a cross-sectional study (much like the National Health and Nutrition Examination Study) for assessing the prevalence, level of awareness, treatment, and control of hypertension in Greece. METHODS: The study was conducted with the collaboration of physicians in 98 Health Centers across Greece. Participants were interviewed about lifestyle, and blood pressure (BP) measurements were taken on two clinical visits for verification of diagnosis and control of hypertension. Hypertension was defined as systolic BP > or =140 mm Hg or diastolic BP > or =90 mm Hg, or current treatment with antihypertensive drugs; the same threshold was used for assessing control of hypertension. RESULTS: A total of 11,950 individuals participated and data for 11,540 were analyzed, comprising 0.1% of the Greek population. The prevalence of hypertension was 31.1% (men 33.6%, women 28.4%); among elderly individuals (>65 years) the prevalence was higher (65.4%). Of the hypertensive individuals, 39.8% did not know that had hypertension, yielding an awareness of 60.2%; in addition, 12.4% were aware but not treated (men 13.1%, women 11.8%). In all, 51.2% (1838) of hypertensive subjects were treated; 67.2% (1235) were treated but not controlled (men 66.7%, women 67.7%); and 32.8% (603) were treated and controlled (men 33.3%, women 32.3%). CONCLUSIONS: The results of the Hypertenshell Study indicate that hypertension is a common risk factor for cardiovascular disease in the Greek population. Awareness, treatment, and control of hypertension are comparable to the best rates of control of hypertension given for the problem, but there is a considerable potential for further improvement in the control of this disease.     

Sildenafil combined with continuous positive airway pressure for treatment of erectile dysfunction in men with obstructive sleep apnea

Objectives To assess efficacy and safety of the combination of sildenafil and continuous positive airway pressure (CPAP), and satisfaction with treatment for erectile dysfunction (ED) in men with obstructive sleep apnea (OSA). Patients and methods Forty men suffering from OSA and concurrent ED were treated with CPAP after a thorough investigation. After a 4-week run-in period, the patients were randomly allocated to treatment for 6 weeks; 20 men to the combination group, receiving additionally 100 mg sildenafil on demand for intercourse, and 20 men to CPAP alone. After a 1-week washout phase, the two groups switched to the other treatment arm for an additional 6 weeks period. End points for efficacy evaluation were the percentage of successful attempts for intercourse based on an event log and the overall satisfaction with sildenafil in the treatment of ED. Results The patients recorded a total of 149 attempts for intercourse during the run-in phase with a success rate of 19.5%. During the 12 weeks of treatment, the success rate of intercourse attempts was 24.8% when only on CPAP and 61.1% when in combination with sildenafil (P < 0.001). Of the studied men, 70% were satisfied with the use of sildenafil while 30% remained unhappy with this additional treatment. Conclusions Sildenafil in combination with CPAP appears clearly superior to CPAP alone. The efficacy of this combination is superior to that of sildenafil alone, as reported in previous studies. Both treatment modalities are safe and well tolerated. However, approximately one-third of the patients remain unsatisfied even from the␣combination treatment. Further treatment options are needed.     

Future options for imatinib mesilate-resistant tumors

The outcome of patients with gastrointestinal stromal tumors has been dramatically improved by therapy with imatinib mesilate (imatinib mesylate), a KIT and platelet-derived growth factor (PDGFR) tyrosine kinase inhibitor. Unfortunately, the majority of patients eventually experience disease progression due to drug resistance. Recent elucidation of the mechanisms of resistance to imatinib, particularly the acquisition of secondary mutations of the KIT and PDGF receptors, has provided significant insight and potential for the development of novel therapies. This review discusses the efficacy of sunitinib, which is approved for the treatment of patients with imatinib-resistant tumors, and highlights a number of emerging second-generation receptor tyrosine kinase inhibitors that show therapeutic potential in imatinib-resistant patients. Also considered are several promising agents targeting pathways downstream of the constitutionally activated KIT and PDGF receptors. Strategies to overcome imatinib resistance by optimizing combination therapy and selecting specific kinase inhibitors based on the secondary mutations identified in tumors of individual patients are presented.     

Elevated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases

The CD40–CD40L costimulatory pathway is involved in the evolution of many autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SS). Increased levels of sCD40L in the serum have been associated with disease activity in SLE. The aim of this study was to investigate the role of sCD40L in the development of lupus nephritis and examine its possible association with cryoglobulinemia in Sjögren's syndrome. We used a 2-site sandwich ELISA to measure the levels of sCD40L in sera, from 64 patients with SLE, RA and SS and 17 healthy blood donors. Biological specimens from the affected tissues such as urine from patients with lupus nephritis and saliva from patients with SS were also tested. In this regard, paired sera and first morning urine samples from 6 SLE patients (3 with active lupus nephritis and 3 with inactive lupus nephritis) were tested with the sCD40L ELISA protocol as well as paired sera and salivary samples from 5 patients with SS and cryoglobulinemia, 5 patients with SS and anti-Ro or anti-La autoantibodies and 5 age-matched healthy control donors. We also examined possible correlations of sCD40L levels with several laboratory and clinical parameters in SS and SLE. We found that sera from SLE and SS patients had significantly higher levels of sCD40L compared to sera from healthy control donors. No sCD40L was detected, in urine samples of patients with either active or inactive nephritis and in salivary samples from SS patients or normal subjects. Soluble CD40L is elevated in sera of SS and SLE patients but further investigation is needed to determine its possible role in SLE nephritis and Sjögren's syndrome.