Elena Bartoloni

Balance between Regulatory T and Th17 Cells in Systemic Lupus Erythematosus: The Old and the New

Pathogenic mechanisms underlying the development of systemic lupus erythematosus (SLE) are very complex and not yet entirely clarified. However, the pivotal role of T lymphocytes in the induction and perpetuation of aberrant immune response is well established. Among T cells, IL-17 producing T helper (Th17) cells and regulatory T (Treg) cells represent an intriguing issue to be addressed in SLE pathogenesis, since an imbalance between the two subsets has been observed in the course of the disease. Treg cells appear to be impaired and therefore unable to counteract autoreactive T lymphocytes. Conversely, Th17 cells accumulate in target organs contributing to local IL-17 production and eventually tissue damage. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent an intriguing and useful tool for SLE treatment in the next future. In this paper, the current knowledge about Treg and Th17 cells interplay in SLE will be discussed.

Inflammatory and autoimmune mechanisms in the induction of atherosclerotic damage in systemic rheumatic diseases: Two faces of the same coin

Introduction For many years, atherosclerosis (ATS) has been regarded as an inevitable, age-related process characterized by the passive accumulation of lipids in the vessel wall. Recently, however, it has become clear that ATS is a dynamic and complex condition and that an inextricable link of multiple pathogenic factors concurs to trigger and perpetuate vessel wall ATS damage. Experimental studies have clearly demonstrated that ATS can be regarded as an inflammatory disease of the arterial intima and that chronic inflammation drives all stages of this condition, including formation, progression, and rupture of atherosclerotic plaque (1,2). To support these observations, acceleration of the ATS process has been described in patients with systemic vasculitides, the typical chronic vascular inflammatory disease, in particular during the active phase of the disease (3). In addition, the finding that patients with connective tissue disease as well as chronic inflammatory rheumatic disorders display an acceleration of clinical and subclinical ATS, even after correction for classic risk factors for cardiovascular disease (CVD), fits well with these observations and further supports the hypothesis that inflammatory and immune-mediated disease-related mechanisms play a pivotal role in the induction of ATS damage (4). It is well established that rheumatoid arthritis (RA), the prototype of inflammatory chronic diseases, and systemic lupus erythematosus (SLE), the classic model of systemic autoimmune disorder, are characterized by a consistent increase of cardiovascular (CV) mortality and morbidity mainly due to an acceleration of atherosclerotic damage and that multiple disease-related pathogenic mechanisms take part in this process (5–8). There is some evidence that both immune dysregulation and systemic inflammatory milieu predating and characterizing earlier phases of RA may be considered important pathogenic factors of vascular impairment (9). Indeed, early RA patients with a disease duration less than 1 year display evidence of subclinical ATS mainly expressed as endothelial dysfunction (9). Moreover, it is interesting to note that the chronic inflammatory cellular infiltrate characterizing RA synovitis displays many intriguing similarities with the cellular infiltration observed in both the damaged arterial wall and atherosclerotic plaque. In this context, blood mononuclear cell recruitment, adhesion molecule up-regulation, and proinflammatory cytokine– and matrix-degrading enzyme production are common mechanisms involved in the initiation and perpetuation of both RA synovitis and atherosclerotic vascular wall lesion (10,11). Similar pathogenic mechanisms have been observed in SLE-associated atherosclerotic damage (12). However, the complex immune system dysregulation characterized by autoantibody production underlying SLE pathogenesis and clinical manifestations seems to play a major role in the induction and acceleration of ATS in these patients (13). An acceleration of the ATS process has also been described in patients with other connective tissue diseases, including primary Sjögren’s syndrome (SS) and systemic sclerosis, although data are less consistent (4,8). In this setting, SS can be considered an interesting and fascinating model of autoimmunity. SS, indeed, predominantly affects young women without traditional CV risk factors and is often characterized by a benign and indolent course not requiring immunosuppressive or corticosteroid therapy that may have a direct or indirect atherogenic effect. Moreover, SS is an autoimmune disease characterized by several clinical manifestations and laboratory markers typical of SLE, such as serositis, Raynaud’s phenomenon, Elena Bartoloni, MD, Roberto Gerli, MD: University of Perugia, Perugia, Italy; Yehuda Shoenfeld, MD: Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel. Dr. Shoenfeld has received consultant fees, speaking fees, and/or honoraria (less than

Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI)

10,000 each) from Bio-Rad DiaSorin, Omrix, and Menarini. Address correspondence to Roberto Gerli, MD, Rheumatology Unit, Department of Clinical & Experimental Medicine, University of Perugia, Via E. Dal Pozzo, I-06122 Perugia, Italy. E-mail: gerlir@unipg.it. Submitted for publication July 1, 2010; accepted August 4, 2010. Arthritis Care & Research Vol. 63, No. 2, February 2011, pp 178–183 DOI 10.1002/acr.20322

Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI)

Objectives To validate the two recently developed disease activity indexes for assessment of primary Sjögrens syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). Methods A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjögrens Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Results Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r=0.59; ESSRPI with PGA: r=0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.

Cardiac involvement in systemic rheumatic diseases: An update

Objectives To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögrens syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). Methods For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients’ satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. Results Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. Conclusions This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

Altered Immunoregulation in Rheumatoid Arthritis: The Role of Regulatory T Cells and Proinflammatory Th17 Cells and Therapeutic Implications

The high rates of cardiovascular (CV) mortality and morbidity observed in patients with systemic autoimmune diseases (SADs) cannot be fully explained by traditional atherosclerosis risk factors as standard therapy (i.e. corticosteroids and methotrexate), cytokines and disease activity may all contribute to accelerated atherosclerosis. There is considerable evidence showing that chronic inflammation and immune dysregulation play a pathogenetic role in the development of atherosclerosis in patients with SADs. Chronic inflammation, accelerated atherosclerosis and functional abnormalities of the endothelium suggest that subclinical CV involvement begins soon after the onset of the disease and progresses with disease duration. All cardiac structures may be affected during the course of SADs (valves, the conduction system, the myocardium, endocardium and pericardium, and coronary arteries), and the cardiac complications have a variety of clinical manifestations. As these are all associated with an unfavourable prognosis, it is essential to detect subclinical cardiac involvement in asymptomatic SAD patients, and begin adequate management and treatment early.

IL-17-producing CD4−CD8− T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjögren's syndrome

In recent years several studies investigated the role of T lymphocyte subpopulations in the pathogenesis of rheumatoid arthritis (RA). Pathogenic Th17 cells mediate pannus growth, osteoclastogenesis, and synovial neoangiogenesis; hence they are key players in the development of the disease. On the other hand, regulatory T (Treg) cells are a T cell subset whose peculiar function is to suppress autoreactive lymphocytes. The imbalance between Th17 and Treg cells has been identified as a crucial event in the pathogenesis of RA. In addition, the effects of currently employed RA therapeutic strategies on these lymphocyte subpopulations have been extensively investigated. This review article aims to discuss current knowledge on Treg and Th17 cells in RA and possible implications of their therapeutic targeting in this disorder.

Diagnostic value of anti-mutated citrullinated vimentin in comparison to anti-cyclic citrullinated peptide and anti-viral citrullinated peptide 2 antibodies in rheumatoid arthritis: An Italian multicentric study and review of the literature

Objectives It has been recently observed that a T-cell subset, lacking of both CD4 and CD8 molecules and defined as double negative (DN), is expanded in the blood of patients with systemic lupus erythematosus, produces IL-17 and accumulates in the kidney during nephritis. Since IL-17 production is enhanced in salivary gland infiltrates of primary Sjögrens syndrome (SS) patients, we investigated whether DN T cells may be involved in the pathogenesis of salivary gland damage. Methods Phenotypic characterisation of peripheral blood mononuclear cells from SS patients and controls was performed by flow cytometry in freshly isolated and anti-CD3-stimulated cells. SS minor salivary glands were processed for immunofluorescence staining. Results CD3+CD4−CD8− DN T cells were major producers of IL-17 in SS and expressed ROR-γt. They were expanded in the peripheral blood, spontaneously produced IL-17 and infiltrated salivary glands. In addition, the expansion of αβ-TCR+ DN T cells was associated with disease activity. Notably, IL-17-producing DN T cells from SS patients, but not from healthy controls, were strongly resistant to the in vitro effect of dexamethasone. Conclusions These findings appear to be of great interest since the identification of a peculiar T-cell subset with pro-inflammatory activity, but resistant to corticosteroids, in an autoimmune disorder such as SS may help to design new specific treatments for the disease.

Cardiovascular disease risk burden in primary Sjögren's syndrome: results of a population‐based multicentre cohort study

In the last years, the detection of antibodies (Abs) against citrullinated peptides (ACPA) has largely replaced rheumatoid factor (RF) as the most helpful biomarker in the diagnosis of rheumatoid arthritis (RA). Current assays detect ACPA reactivity with epitopes on various different citrullinated proteins. Among these, anti-cyclic citrullinated peptide (CCP) Abs have been widely demonstrated to be an important diagnostic and prognostic tool because of their high specificity. Recently, citrullinated vimentin, a protein highly released in synovial microenvironment, has been identified as potential autoantigen in the pathophysiology of RA and an enzyme-linked immunosorbent assay (ELISA) for the detection of Abs directed against a mutated citrullinated vimentin (anti-MCV) was developed. Several recent studies evaluating the characteristics of anti-MCV in comparison to anti-CCP Abs, have given conflicting results. Anti-MCV have been demonstrated to perform better than anti-CCP as predictor of radiographic damage. Conversely, its additional diagnostic and prognostic role in comparison to anti-CCP in both early and established RA is controversial. Aim of this study was to evaluate the diagnostic performance of anti-MCV in RA and to compare it to anti-CCP and the recently developed assay targeting viral citrullinated peptide 2 (VCP2) in a large cohort of RA patients (n=285), healthy subjects and other disease controls (n=227). Anti-MCV resulted to have a sensitivity of 59% and a specificity of 92%. In comparison, anti-CCP and anti-VCP2 displayed a sensitivity of 77% and 61% and a specificity of 96% and 95%, respectively. Of interest, at the manufacturer recommended cutoff value of 20U/mL, a high percentage of healthy subjects as well as Epstein Barr (EBV) and hepatitis C (HCV) virus infected patients resulted anti-MCV positive. In our large cohort of RA patients, anti-MCV demonstrated lower sensitivity than anti-CCP and VCP2 test, thus not allowing to confirm previously published data. Moreover, the high rate of detection in infectious diseases limits its diagnostic value in undifferentiated arthritis.

Diagnosis and classification of autoimmune hypophysitis

Systemic autoimmune diseases, in particular systemic lupus erythematosus and rheumatoid arthritis, are characterized by a high risk of premature cardiovascular (CV) events. Disease‐related characteristics and traditional CV disease risk factors may contribute to atherosclerotic damage. However, there are limited data on the risk of overt CV events in primary Sjögrens syndrome (pSS).