The association between duration of remission, fatigue, depression and health-related quality of life in Italian patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the impact of duration of remission on the health-related quality of life (HRQoL) of patients with systemic lupus erythematosus (SLE). METHODS: We conducted a 5-year retrospective study on two Italian cohorts. Remission was defined as a continuative period of no clinical disease activity, according to the Systemic Lupus Erythematosus Disease Activity Index 2 K, and a permitted maximum prednisone dose of 5 mg/day. HRQoL was measured using the 36-Item Short-Form Health Survey (SF36) during the last visit. RESULTS: We enrolled 136 female SLE patients. During observation, 15 (11%) patients had been in remission for ≥1 and <2 years, 15 (11%) for ≥2 and <3 years, 19 (14%) for ≥3 and <4 years, 9 (7%) for ≥4 and <5 years, and 53 (39%) had been in prolonged remission for ≥5 years. In the multivariate model, considering depression and fatigue as covariates, patients in prolonged remission showed significantly better scores in the physical functioning (p = 0.039), role physical (p = 0.029), bodily pain (p = 0.0057), general health (p = 0.0033) and social functioning (p = 0.0085) components of the SF36, compared with those in remission <5 years or unremitted. Subsequent mediation analyses found that these effects were partly influenced by depression. CONCLUSION: Lupus remission could improve the HRQoL of SLE patients, particularly when associated with appropriate management of depression and fatigue.

Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome.

BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. METHODS: We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at - 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. RESULTS: We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbß3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. CONCLUSIONS: In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS.

Is fatigue a cause of work disability in systemic lupus erythematosus? Results from a systematic literature review.

OBJECTIVE: Fatigue affects the almost totality of Systemic Lupus Erythematous (SLE) patients impairing physical function and leading to a strong reduction of health-related quality of life (HRQoL). Similarly, SLE patients have an increased rate of work loss and work limitations. The aim of our paper was to systematically assess the relationship between fatigue and work disability in SLE. MATERIALS AND METHODS: We performed a systematic review using the terms "fatigue" and "employment", "work disability", "work impairment", "presenteeism" and "absenteeism." RESULTS: 19 studies were identified. Fatigue was involved in the development of work loss. In employed patients, fatigue led to impairment of work productivity and presenteeism with a parallel increase of both direct and indirect health costs. Fatigue also affected parenting and household productivity. CONCLUSIONS: An adequate control of fatigue could improve physical and work performance in SLE patients thus reducing rates of work loss.

Inflammation as a mediator of the association between osteoporosis and hearing loss in older subjects: a population-based study.

OBJECTIVE: Due to the aging of populations, the prevalence of hearing loss and osteoporosis is increasing. Previous studies have found an association between these conditions. Nevertheless, the pathophysiologic pathway of such an association has not yet been established. The present study aimed at evaluating the association, if any, of hearing loss with osteoporosis in an older unselected population, and whether this association varied according to inflammatory status. PATIENTS AND METHODS: We assessed the association of osteoporosis with a self-reported hearing loss in all 310 subjects aged 75+ living in Tuscania (Italy), without exclusion criteria. Bone density was assessed by calcaneal quantitative ultrasound; osteoporosis was defined as a T-score ≤ -2.5 Standard Deviation. RESULTS: Hearing loss was associated with osteoporosis (OR = 1.84, 95% CI = 1.03-3.28; p = 0.40) in multivariable logistic regression analysis, after adjusting for potential confounders. Analysis of the interaction term indicated that this association varied according to the erythrocyte sedimentation rate, ERS (p = 0.030), and high-sensitivity C reactive protein, hs-CRP (p = 0.017) but not sex (p = 0.832). Of notice, this association was significant only for higher levels of inflammatory parameters (OR = 2.82; 95% CI = 1.15-6.90; p = 0.023 for the higher ERS tertile; and OR = 3.81; 95% CI = 1.36-10.63; p = 0.011 for the higher hs-CRP tertile vs. lower tertiles). CONCLUSIONS: Hearing loss is associated with osteoporosis in community dwelling elderly. Such an association seems to depend upon higher inflammation levels.

Primary prevention of cardiovascular disease in patients with systemic lupus erythematosus: case series and literature review.

Background Systemic lupus erythematosus is associated with an increased risk of cardiovascular disease. Low-dose aspirin, hydroxychloroquine and statins have been suggested to play a prophylactic role of cardiovascular events. This study is devoted to reviewing the literature on the topic and assessing the effects of these drugs in preventing a first cardiovascular event in a two-centre Italian series. Methods A PubMed search on cardiovascular prevention in systemic lupus erythematosus was performed. Moreover, systemic lupus erythematosus patients admitted to two centres from 2000-2015, who at admission had not experienced any cardiovascular event, were investigated. Aspirin, hydroxychloroquine and statin use, and the occurrence of any cardiovascular event, were recorded at each visit. Kaplan-Meier and Cox regression analyses were performed to evaluate the role of traditional, disease-related cardiovascular risk factors and of each of the three drugs in the occurrence of new cardiovascular events. Results The literature search produced conflicting results. Two hundred and ninety-one systemic lupus erythematosus patients were included in the study and followed for a median of eight years. During follow-up, 16 cardiovascular events occurred. At multivariate analysis, taking aspirin (hazard ratio: 0.24) and hydroxychloroquine for more than five years (hazard ratio: 0.27) reduced, while antiphospholipid antibody positivity (hazard ratio: 4.32) increased, the risk of a first cardiovascular event. No effect of statins emerged. Conclusion Our study confirms an additive role of aspirin and hydroxychloroquine in the primary prophylaxis of cardiovascular events in Italian patients with systemic lupus erythematosus. The lack of any detected effect in previous reports may depend on the design of studies and their short follow-up period.

The IL33/ST2 axis in Sjogren syndrome in relation to disease activity.

OBJECTIVE: Primary Sjogren's Syndrome (pSS) is a systemic autoimmune disorder characterized by infiltration of the exocrine glands leading to secretory insufficiency. Despite the progress made in understanding the pathogenesis of the SS, many aspects remain to be clarified. Interleukin-33 (IL33) is a recently discovered cytokine, belonging to IL-1 superfamily. IL33 and its soluble receptor ST2 were implied in a number of immune and in autoimmune diseases pathogenesis. In this work ,we analyzed expression of IL33 and ST2 in Sjogren's syndrome. PATIENTS AND METHODS: Serum IL-33 and soluble ST2 were analyzed using commercial ELISA kit in 15 pSS, 9 patients with Systemic Lupus Erythematosus and 9 controls. RESULTS: We found significant hyperexpression of sST2 in sera of SS patients and SLE patients compared to healthy subjects (p = 0.04 and p = 0.07, respectively). In pSS, sST2 levels in pSS positively correlated with activity index SSDAI (r = 0.662, p = 0.007). In SLE, we found positive correlation between ST2 and SLEDAI 2K (r = 0.685, p = 0.04). Circulating levels of IL-33 were detectable in 2 of 15 SS patients, in 2 SLE patients and in 1 of control subjects. CONCLUSIONS: We found an hyperexpression of sST2 in pSS and SLE patients with a possible immune modulatory role, because of a substantial suppression of circulating IL33. In our pSS and SLE cohort, sST2 levels were in correlation with disease activity indices.

Relationship between leptin and regulatory T cells in systemic lupus erythematosus: preliminary results.

OBJECTIVE: Crescent literature data demonstrated a role of adipokines in immune responses, particularly leptin is involved in wide spectrum of pro-inflammatory functions. Several evidences suggested that leptin is able to inhibit T regulatory cells proliferation and function in vitro models. In the present study, we investigate the relationship between leptin and circulating T regulatory cells (Tregs) in patients affected by systemic lupus erythematosus (SLE). PATIENTS AND METHODS: 13 SLE patients and 11 healthy controls were enrolled. Metabolic syndrome and cardiovascular parameters were evaluated. Serum leptin levels were detected by commercial ELISA kit and circulating regulatory T cells were determined by FACS analysis as CD4+CD25highFOP3+ lymphocytes. RESULTS: Metabolic syndrome, defined by ATPIII criteria, was more prevalent in SLE compared to controls (38.4% vs. 0%, p = 0.04), as well as arterial hypertension (38.4% vs. 0%, p = 0.04). We did not find significant differences in mean leptin levels among SLE and controls (13.13 ± 1.51 ng/ml vs. 9.48 ± 8.67 ng/ml, p = 0.6). Mean Tregs percentage of total CD4 were 1.27 ± 0.9 in SLE vs. 2.8 ± 1.2 in healthy controls (p = 0.001). We found a negative correlation between leptin levels and Tregs percentage of total CD4 in SLE patients (r = 0.4, p = 0.01). CONCLUSIONS: Our results suggest a role of leptin in the regulation of circulating T regulatory cells amount in human SLE.

Granzyme B-induced mitochondrial ROS are required for apoptosis.

Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GB-mediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis.

Subclinical carotid atherosclerosis in elderly patients with primary Sjögren syndrome: a duplex Doppler sonographic study.

A growing body of evidence presents a link between chronic inflammatory rheumatic diseases and atherosclerosis. To evaluate subclinical carotid atherosclerosis in an elderly group of patients with primary Sjögren syndrome compared with a control group matched for age, sex, ethnicity and cardiovascular risk factors, we enrolled 18 patients with Primary Sjögren Syndrome (mean age 65 ± 5.93 SD) and 18 mild Ostheoarthritic patients (mean age 66 ± 5.94 SD) from the outpatient department of Rheumatology, University “Campus Bio-Medico, Rome, Italy, matched for age, sex, ethnicity and cardiovascular risk factors. A duplex Doppler sonographic study of carotids was performed in order to evaluate intima-media thickness (IMT), stiffness and haemodynamic parameters [resistivity and pulsatility indices (RI and PI, respectively)]. No significant difference was found between primary Sjögren syndrome and control patients in IMT, stiffness and haemodynamic parameters. The lack of significant difference in subclinical atherosclerosis between elderly primary Sjögren syndrome and control matched patients, indicates that traditional cardiovascular risk factors, immunologic alterations and chronic inflammation do not influence the progression of vascular damage in the carotid circulation of patients with median disease duration of 6.5 years.

Systemic lupus erythematosus patients with and without neuropsychiatric manifestations: a neck and transcranial duplex sonography study.

Neuropsychiatric manifestations are not rarely associated with systemic lupus erythematosus (SLE). Magnetic resonance angiography and positron emission tomography can provide excellent images of cerebral perfusion and metabolism whereas information is still lacking on a possible diagnostic role of ultrasound. In this study we aim to assess whether duplex sonography of neck and intracranial vessels may be useful in distinguishing patients with and without neuropsychiatric SLE (NPSLE). Neck and transcranial duplex sonography was performed by a single operator on 33 women affected by SLE (mean age +/- SD: 47.69+/-8.17 years) and on 15 healthy control subjects. Nineteen patients presented NPSLE. Pulsatility and resistivity indices (PI and RI) were automatically calculated by the ultrasound instrument in internal carotid (ICA) and middle cerebral artery (MCA), on both sides, according to standard methods. No significant haemodynamic differences were found in mean and median PI and RI values of ICA and MCA comparing SLE with NPSLE patients and with healthy control subjects. No correlation was found between MCA and ICA parameters in the same group of patients. Duplex sonography of cerebral vessels is unable to distinguish SLE and NPSLE patients. Heterogeneity of causes in the pathogenesis of NPSLE and the different vascular adaptation of cerebral macrocirculation as opposed to cerebral microcirculation may represent possible reasons that explain the inability of ultrasound to differentiate SLE patients from NPSLE patients.

Cytokines expression in SLE nephritis.

Renal involvement is a common manifestation in course of systemic lupus erythematous (SLE) and may occur at any time. In SLE nephritis, the pattern of glomerular injury is primarily related to the formation of the immune deposits in situ, due major to antidouble-stranded DNA (anti-dsDNA) antibodies and anti- C1q. Immune complexes deposits can induce the inflammatory response by activation of adhesion molecules on endothelium, resulting in the recruitment of pro inflammatory leukocytes. Activated and damaged glomerular cells, infiltrating macrophages, B and T cells produced cytokines that play a pivotal role as inflammatory mediators to extend renal injury. In serum of SLE patients, the concentrations of IL-6, IL-17, IL-12, INF-gamma, IL-18, IL-10 and TNF-alpha are higher than healthy people and this increase correlate with disease activity. It is well established possible correlation between urinary cytokines levels (IL-6, IL-10, INF-gamma and TGF-beta) and disease activity. In fact, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) correlate with cytokines over-expression, in particular IL-17, IL-10, TNF-alpha and the axis INF-gamma/IL-12. Recent studies are promising about proteinuria reduction and improving renal function through cytokine blockade therapy.

Apoptosis and autoimmunity induced by clodronate in systemic lupus erythematosus mononuclear circulating cells.

The aim of this study is to evaluate the effect of clodronate on apoptosis of human systemic lupus erythematosus circulating mononuclear cells and to analyze possible correlations with changes in autoantibody production in vitro. Lympho-monocytes from 20 SLE patients were isolated and incubated with or without addition of 1 microM clodronate for 72 hours. Apoptosis and release of genomic material was assessed by immunofluorescent detection of cleaved caspase-3 and by Cell-Death-Detection ELISAPLUS kit (Roche). Anti-Nucleosome IgG and anti-dsDNA IgM and IgG autoantibody levels were determined in supernatants by commercially available ELISA kits. Clodronate induced apoptosis in monocytes as confirmed by cleaved caspase-3 immunostaining and by quantification of cleaved nucleosome in the supernatants (treated 0.22+/-0.05 O.D. vs untreated 0.09+/-0.04 O.D.; P less than 0.001). This finding was coupled with a significant increasing in supernatants of IgG anti-Nucleosome (treated 6.5+/-1.1 vs untreated 5.5+/-0.6 IU/mL; p=0.001) and IgM (treated 3.0+/-1.3 vs 2.2+/-0.9 IU/mL; p=0.02) and IgG (treated 4.0+/-1.8 vs untreated 2.8+/-1.5 IU/mL; p=0.02) anti-dsDNA autoantibody levels. Our findings stressed the pro-apoptotic activity of clodronate, as well as its potential autoimmunity induction in SLE mononuclear circulating cells. Clinical studies could clarify the role of bisphosphonates on autoantibody production and worsening of disease activity.

[BAFF/APRIL pathway in Sjögren syndrome and systemic lupus erythematosus: relationship with chronic inflammation and disease activity]. / Pathway BAFF/APRIL nella sindrome di Sjögren e nel lupus eritematoso sistemico: relazione con infiammazione cronica e attività di malattia.

OBJECTIVES: BAFF and APRIL belong to the tumor necrosis factor (TNF) superfamily and are crucial for the survival, maturation, and differentiation of B cells. Aim of the study is to evaluate BAFF and APRIL in patients affected by Sjögren syndrome (SS) and systemic lupus erythematosus (SLE). METHODS: Sixty patients, (40 SLE, 20 SS) and 20 healthy subjects were enrolled in this study. All subjects were evaluated for laboratory data (ESR, CRP, immunoglobulin G, A and M, complement fragments C3 and C4, LDH, beta2microglobulin, serum levels of rheumatoid factor), autoantibodies (ANA; ENA-SSA, -SSB, -Sm) and lymphocytes subpopulations. For patients, disease activity and damage indexes were assessed with the use of SLEDAI and SLICC and SSDAI and SSDDI for SLE and SS, respectively. BAFF and APRIL were determined by commercial sandwich ELISA kit (R&D Systems, Bender MedSystem). Statistical analysis has been performed with software Prism (Graphpad Instat, version 5.00). RESULTS: APRIL levels were higher among SLE and SS patients compared to controls (p<0.0001, and p0.0001, respectively). BAFF levels in SLE were significantly higher than in SS (p<0.0001). We found higher BAFF levels in SLE and SS compared to controls (p<0.0001). Among SLE patients APRIL correlated with SLEDAI (r 0.3, p 0.04), SLICC (r 0.5,p 0.001), ESR (r 0.3, p 0.005) and CRP (r 0.4, p 0.02). Among SS patients APRIL correlated with SSDAI (r 0.4, p 0.02), SSDDI (r 0.4, p0.01), IgG (r 0.5, p0.01), ESR (r 0.6, p 0.01), CRP (r 0.6, p 0.02) and CD19 B lymphocytes absolute count (r 0.4, p 0.04); BAFF correlated with SSDDI (r 0.7, p 0.004) and CD19 B lymphocytes absolute count (r 0.5, p 0.04). CONCLUSIONS: In this study we showed a correlation between disease activity, damage indexes and BAFF/APRIL levels in SLE and SS patients suggesting a role in the strong activation of the immune system in patients with active disease.

Stiffness parameters, intima-media thickness and early atherosclerosis in systemic lupus erythematosus patients.

Detection of early carotid vascular disease in patients with systemic lupus erythematosus (SLE) is considered mandatory for evaluation of subclinical atherosclerosis (ATS), and various ultrasonographic (US) parameters have been proposed. In the present investigation, 33 SLE and 33 healthy age-matched females have been studied by colour-coded sonography of the common carotid artery, assessing intima-media thickness (IMT), vascular strain (VS), vascular distensibility (VD), vascular stiffness (VSf) and pressure-strain elastic modulus (PSEM) as possible markers of early ATS. Patients with SLE, despite equivalent exposure to "traditional" cardiovascular risk factors, presented a higher mean IMT of the common carotid artery than healthy subjects (0.7 +/- 0.2 mm vs 0.5 +/- 0.1 mm - P < 0.0001). Of the stiffness parameters, patients with lupus showed a mean VSf of 0.72 +/- 0.38 vs 0.54 +/- 0.14 in controls (P < 0.0001) and a mean PSEM of 6.0 +/- 2.8 Pa vs 3.0 +/- 1.4 Pa in controls (P < 0.0001). Mean VS and VD were significantly lower in patients with SLE than in healthy subjects (P < 0.0001). Among individuals with IMT < 0.6 mm, patients with SLE presented more compromised stiffness parameters. IMT was shown to be a useful parameter in the evaluation of vascular damage, even in a "sub-clinical" phase, while stiffness parameters provide additional details regarding endothelial and vessel functional state. Combined evaluation may allow ATS to be detected in the early stages in patients with SLE.