Gender equality in Rheumatology.

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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.

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.

Recognition of Ii-Key/MHC class II epitope hybrids derived from proinsulin and GAD peptides by T cells in type 1 diabetes.

In order to determine whether the Ii-Key technology can enhance the presentation of specific epitopes associated with type 1 diabetes, we have designed and synthesized a series of Ii-Key/proinsulin and GAD epitope hybrid peptides. Peptides of proinsulin and GAD shown to be recognized by CD4+ T cells of type 1 diabetes patients have been selected from the literature and modified with Ii-Key. A total of 23 Caucasian type 1 diabetes subjects and 17 normal subjects as controls were included in the study. Reactive T cells were identified using an IFN-γ ELISPOT assay. We selected 5 proinsulin and 5 GAD epitopes. Regarding the activity of the proinsulin Ii-Key hybrids, 3 out of 15 patients (20%) demonstrated a positive response to one or more Ii-Key hybrid peptides compared to no responders in the control subjects. Two out of 8 patients demonstrated a positive response to one or more Ii-Key/GAD65 hybrids. Proinsulin Ii-Key hybrids and peptides were recognized only by DR3/DR4 0302+ve diabetic patients. Control subjects showed no detectable response to stimulation with Ii-Key hybrids or peptides, neither for proinsulin nor GAD65. We have now shown that the use of Ii-Key-modified MHC class II epitopes, derived from proteins associated with insulin-secreting cells, can detect the presence of specifically activated CD4+ T helper cells with greater sensitivity than unmodified epitopes in the standard ELISPOT assay. The use of these technologies may be of use in identifying patients at the earliest stages of type 1 diabetes.

[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.

Antibodies to carbonic anhydrase in patients with connective tissue diseases: relationship with lung involvement.

The aim of this study is to evaluate the presence of antibodies to carbonic anhydrase I and/or II (ACAI and ACAII) in patients affected by connective tissue diseases (CTD) and to investigate their association with lung involvement evaluated by High resolution CT scan (HRCT). Ninety-six patients affected by CTD were studied, i.e. 33 rheumatoid arthritis (RA), 8 psoriatic arthritis (PA), 8 ankylosing spondilitis (AS), 23 Systemic Lupus Erythematosus (SLE), 10 Sjogren Syndrome (SS), and 14 Systemic Sclerosis (SSc). ACA were detected by ELISA. The lung involvement was evaluated by means of a previously described HRCT score. According to a receiver operator characteristic curve, patients were divided into those with HRCT score > or = 10 and those with HRCT score < 10, where HRCT score > or = 10 was predictive of interstitial lung disease. ACAI and/or ACAII were detected in 30/96 patients (31.2%) (P < 0.0001 in comparison with controls). In particular, the prevalence of ACAI and/or ACAII was significantly higher in patients with RA (P = 0.002), PA (P < 0.0001), SLE (P = 0.0003) and SSc (P < 0.0001). A positive correlation was found between HRCT scores and CRP or ACAI levels (P = < 0.0001 and P = 0.004, respectively). Thirty-nine of 96 patients (40.6%) showed a HRCT score > or = 10 and both their CRP and ACAI levels were significantly higher when compared with patients showing a HRCT score less than 10 (P < 0.0006 and P = 0.0009, respectively). Moreover, C3 and C4 complement fractions inversely correlated with HRCT scores (P = 0.0004 and P < 0.0001, respectively) and lower values of C3 and C4 complement fractions were found in patients with HRCT score > or = 10 than in those with HRCT score less than 10 (P = 0.014 and P = 0.007, respectively). Due to the lower levels of complement fractions detected in patients with HRCT score > or = 10, a possible immune-complex-mediated pathogenic mechanism of lung involvement could be suggested.

Antinuclear antibodies prevalence in Filipinos migrated to Italy.

Antinuclear antibodies (ANA) represent the main diagnostic markers for systemic autoimmune disease (AD), although their presence can be detected in blood donors. The aim of this study was to study ANA prevalence in healthy subjects of different racial groups, exposed to the same environmental factors, in order to understand the relevance of genetics or environment in determining autoimmunity. We enrolled in this study 80 healthy Filipinos (Polynesian), migrated to Italy from an average of 15 years, and 60 healthy native Italians (Caucasian) and ANA were detected in their sera (at 1:80 screening dilution) through indirect immunofluorescence assay. We found a higher prevalence of ANA positivity in Filipinos compared to Italians (23.7% vs 8.3%--P = 0.02; OR 3.43; 95% CI 1.2-9.8), above all in females and elderly, although demographic characteristics, clinical history and habits were not significantly different between the two groups. These data confirm that ANA positivity is not a rare condition and healthy non-Caucasians present a higher prevalence of autoantibodies. This could be determined by their autoimmunity-prone immune system or by the exposition to infective agents, pollution, drugs or nutrition of a western country. Future studies to evaluate the ANA prevalence in Filipinos in their own country and the follow-up of positive patients could clarify the real predisposition to AD of this population.

[Alexithymia and immunoendocrine parameters in patients affected by systemic lupus erythematosus and rheumatoid arthritis]. / Alessitimia e pathway immunoendocrino nel lupus eritematoso sistemico e nell'artrite reumatoide.

OBJECTIVE: Aim of this study was to evaluate the prevalence of alexithymia in patients affected by SLE or RA and to investigate the correlation between alexithymia and immunoendocrine parameters (PRL, hGH, IL-6 and TNF-alfa). METHODS: Twenty-five patients (12 and 13 affected by SLE and RA, respectively) were enrolled into the study. The Toronto Alexithymia Scale-20 (TAS-20) was administered. PRL, hGH, IL-6 and TNF-alfa levels were measured by commercially available ELISA kits. RESULTS: Alexithymia prevalence (TAS-20 > or = 51) was 54% in RA and 42% in SLE patients. hGH serum levels were 3.1+/-4.2 and 1.1+/-0.9 IU/ml in SLE and RA, respectively. PRL concentration was 18.4+/-6.5 ng/ml and 14.2+/-4.0 ng/ml in SLE and RA patients, respectively (p=0.03). In RA group, TNF-alpha was 20+/-36.2 whereas in SLE it was 4.9+/-12.8 pg/ml (p=0.03); IL-6 serum concentrations were 24.4+/-25.1 and 2.9+/-5.4 pg/ml, in RA and SLE respectively (p=0.004). The serum level of hGH showed slight increase in alexithymic group (A) compared to non alexithymic group (NA) in both SLE and RA patients. PRL serum levels in SLE-A patients was 26.7+/-17.3 ng/ml while in SLE-NA patients was 12.4+/-3.3 ng/ml (p=0.04). In RA patients increased values of IL-6 and TNF-alpha were present in the A group compared to NA group (IL-6: 35.3+/-28 pg/mL vs 3.5+/-3.9 pg/mL, p=0.01; TNF-alpha: 34.7+/-39 pg/mL vs 3.1+/-3.4 pg/mL, p=0.01). CONCLUSIONS: In this preliminary results we found an high prevalence of alexithymia and a correlation between immunoendocrine parameters and alexhytimic features in SLE and RA, suggesting that an immunomodulatory pathway could influence this cognitive style in patients with autoimmune disorders. Other studies should contribute to find a common biological pathway linking alexithymia and autoimmunity.

Spontaneous splenorenal shunt in a patient with antiphospholipid syndrome: the first case reported.

The antiphospholipid syndrome (APS) is an autoimmune disorder, characterized by a wide spectrum of clinical manifestations. Thromboembolic events, with a greater involvement of extremities veins, are the most common features, and obstruction of abdominal vessels are sporadically reported. We present a singular case of a patient with primary APS (PAPS) that developed a spontaneous splenorenal shunt, secondary to a total portal, mesenteric and splenic vein thrombosis. Spontaneous splenorenal shunt, an uncommon circumstance reported in cirrhotic disease, to the best of our knowledge, has not been previously described in PAPS.

Prevalence of interstitial lung involvement in patients with connective tissue diseases assessed with high-resolution computed tomography.

OBJECTIVES: To assess the prevalence of interstitial lung disease (ILD) in patients with different forms of connective tissue disease (CTD) using non-invasive procedures including high-resolution computed tomography (HRCT) and to evaluate the relationship between the imaging and functional status of the patients. METHODS: Eighty-one subjects with CTD (47 inpatients and 34 outpatients) were evaluated with pulmonary function tests (PFT) and radiological investigations. The extent and severity of lung disease was quantified with an HRCT scoring system previously used in patients with systemic sclerosis (SSc). Interstitial lung involvement was defined as predominantly fibrotic or inflammatory based on HRCT abnormalities. RESULTS: HRCT abnormalities suggestive of ILD were observed in 69 patients (85.1%), whereas PFT and plain radiograph alterations occurred less frequently (40.7%). The most frequent HRCT abnormalities were septal/subpleural lines and ground-glass appearance whereas lesions consistent with advanced fibrosis were observed in a minority of patients. The HRCT score was higher in patients with abnormal PFT (p<0.001). Thirty-five patients had predominant fibrosis and 34 patients predominantly inflammatory abnormalities. A score of 10 points represented the best compromise between sensitivity and specificity in predicting functional impairment. CONCLUSIONS: A high prevalence of ILD was found based on HRCT abnormalities. However, HRCT scans characterized by minor abnormalities have poor specificity for clinically significant disease and functional findings should also be considered. The large number of patients with predominantly inflammatory HRCT abnormalities suggests that many cases of ILD may be diagnosed in a relatively early stage of the disease.

[Neuropsychiatric lupus erythematosus]. / Il lupus neuropsichiatrico.

Neuropsychiatric involvement in patients with Systemic Lupus Erythematosus (SLE), first mentioned by Kaposi more than 100 years ago, still remains one of the main challenge facing rheumatologist and other physicians. The diagnosis of neuropsychiatric SLE (NPSLE) is complex not only because of the considerable prevalence variation (14-80%) but also because of the wide spectrum of NP manifestations. They vary from overt neurologic alterations (seizure, psychosis), to subtle abnormalities (neurocognitive dysfunctions). Different NP manifestations result from a variety of mechanisms including antibodies, vasculitis, thrombosis, hemorrhages and cytokine-mediated damages. Of note, despite the dramatic clinical manifestations, too often changes at the morphological neuroimaging techniques are minimal and non specific. There is no one diagnostic tool specific for NPSLE and diagnosis must be based on the combinated use of immunoserological tests, functional and anatomical neuroimaging and standardized specific criteria. Symptomatic, immunosuppressive and anticoagulant therapies are the main strategies available in the management of these patients. Therapy for CNS lupus should be adjusted according to the needs of the individual patients. The coming years promise to be an important time for the development of new neuroimaging techniques and for the study of disease mechanism. An early and objective identification of brain involvement will allow for appropriate treatment to avoid severe complications.

The adjunctive role of antiphospholipid antibodies in systemic lupus erythematosus cardiac involvement.

OBJECTIVE: To evaluate the prevalence of cardiac alterations by trans thoracic echocardiography (TTE) and the possible role of aPLs in determining heart damage in SLE patients. PATIENTS AND METHODS: We investigated 34 consecutive Caucasian SLE patients and 34 age and sex- matched controls. All patients underwent TTE. Lupus anticoagulant (LA) was assayed. IgG and IgM antiphospholipid antibodies against cardiolipin (aCL), phosphatidylinositol (aPI), phosphatidylserine (aPS), phosphatidic acid (aPA), and anti-Beta2-glycoprotein I antibodies (aBeta2GPI) were determined by ELISA. RESULTS: Nineteen (56%) SLE patients showed at least one cardiac abnormality (P < 0.0001 - RR 19; OR 41.8; 95% CI 5.1-342). The predominant valve dysfunctions were represented by mitral (21%) and tricuspidal (18%) regurgitation. Aortic regurgitation was observed in 12% of patients, pericardial effusion and left atrial enlargement were identified in 15% and 12% of cases, respectively. Mitral valvular strands were detected in one patient. The prevalence of cardiac abnormalities correlated with disease duration. Echocardiographic alterations were more common in aPLs positive than in aPLs negative patients (P = 0.02 - RR 2.5; OR 6.1; 95% CI 1.2-30.1). Patients with IgG-aPA, -aPI and -aPS had a higher prevalence of left atrial enlargement (P < 0.05); IgG-aPA and -aPI were significantly associated with increased interventricular septum thickness (P < 0.05). CONCLUSION: Our findings confirm that the heart is one of the main target in SLE patients. The association between aPLs and cardiac impairment suggests an adjunctive role of these autoantibodies in determining heart damage. SLE vasculopathy is a multifactorial process leading to accelerated atherosclerosis. Heart involvement over the course of disease requires a comprehensive screening and management of traditional and new cardiovascular risk factors to prevent cardiac damage, which represents the primary cause of morbidity and mortality in SLE patients.

Alexithymia and neuroendocrine-immune response in patients with autoimmune diseases: preliminary results on relationship between alexithymic construct and TNF-alpha levels.

Alexithymia is conceptualized as a disorder of emotion regulation mechanisms, which involves a dissociation of emotional and physical responses to life events and bodily sensations. Our results might suggest a possible relationship between the alexithymic construct and TNF levels in RA patients. These preliminary findings corroborate the integrated bidirectional interactions between neuropsychological mechanisms and the neuroendocrine-immune system in patients affected by autoimmune diseases and contribute to finding a common biological pathway linking alexithymia and autoimmune-inflammatory diseases.

Raynaud's phenomenon and antiphospholipid antibodies in systemic lupus erythematosus: is there an association?

OBJECTIVE: To evaluate the association of IgG and IgM antibodies directed against different negatively charged phospholipids (that is, anticardiolipin (aCL), antiphosphatidylinositol, antiphosphatidylserine, and antiphosphatidic acid) and anti-beta(2)-glycoprotein I (abeta(2)GPI), with Raynaud's phenomenon in patients with systemic lupus erythematosus (SLE). METHODS: Ninety three patients with SLE (81 female), 40 with and 53 without Raynaud's phenomenon, were included in the study. IgG and IgM antiphospholipid antibodies and abeta(2)GPI were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: Fifty patients (54%) were positive for IgG and/or IgM antibodies to one or more phospholipid antigens or to beta(2)GPI. The prevalence of all autoantibodies evaluated, either IgG or IgM, was higher in patients without than in those with Raynaud's phenomenon. A negative association was found between IgG aCL and Raynaud's phenomenon (p=0.038), whereas autoantibodies other than aCL were not significantly associated with Raynaud's phenomenon. CONCLUSION: Our results demonstrate no positive association between antiphospholipid antibodies and Raynaud's phenomenon in SLE and indicate that measurement of anti-negatively charged phospholipid antibodies other than aCL is not useful as a serological marker predictive for Raynaud's phenomenon.

Neurological involvement in antiphospholipid antibodies syndrome (APS).

Antiphospholipid antibodies (aPL) have been most strongly associated with a syndrome (APS) characterized by venous and/or arterial thrombosis, thrombocytopenia, recurrent fetal losses and a variety of non-thrombotic and thrombotic neurological disorders. Cerebral ischemia associated with aPL is the most common arterial thrombotic manifestation. Other neurological syndromes, such as cognitive dysfunction, dementia, psychosis, depression, seizures, chorea and transverse myelopathy, have all been associated with antiphospholipid antibodies.