Rheumatoid Arthritis: Sherer Y

Harel-Meir M, Sherer Y, Shoenfeld Y. · Department of Medicine 'B', Chaim Sheba Medical Center, Tel-Hashomer, Israel. · Nat Clin Pract Rheumatol. · Pubmed #18037930 No free full text.

Abstract: Autoimmune rheumatic diseases are considered to be influenced by both genetic and environmental factors. Tobacco smoking has been linked to the development of rheumatic diseases, namely systemic lupus erythematosus and rheumatoid arthritis, and has been shown to interact with genetic factors to create a significant combined risk of disease. Smoking also affects both the course and the outcome of rheumatic diseases. Smoking increases the risk of dermatologic features and nephritis in systemic lupus erythematosus, rheumatoid nodules and multiple joint involvement in rheumatoid arthritis and digital ischemia in systemic sclerosis, as well as further increasing the risk of accelerated atherosclerosis in these diseases. Smoking is known to modulate the immune system through many mechanisms, including the induction of the inflammatory response, immune suppression, alteration of cytokine balance, induction of apoptosis, and DNA damage that results in the formation of anti-DNA antibodies. No sole mechanism, however, has been linked to any of the autoimmune illnesses, which therefore complicates full comprehension of the 'smoking effect'. Further studies, perhaps using animal models, are needed to analyze the exact effect of smoking on each disease separately.

Gerli R, Sherer Y, Bocci EB, Vaudo G, Moscatelli S, Shoenfeld Y. · Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy. · Ann N Y Acad Sci. · Pubmed #17894000 No free full text.

Abstract: The risk of cardiovascular (CV) disease increases in patients with rheumatoid arthritis (RA). This is due to a number of different triggers including traditional and disease-related factors. Among established risk factors for CV disease, smoking may exert a more dangerous effect on arterial wall in RA than in the general population by a synergic effect with inflammatory processes of the disease. Although persistent inflammation and immune dysregulation of RA may contribute to favor other well-known CV risk factors, such as dyslipidemia, it is now clear that the disease itself represents an independent risk factor for CV disease by the action of RA chronic inflammatory process as well as humoral and cell-mediated immune mechanisms. There is evidence that CV risk is associated with severity and extension of the disease and it is of interest the fact that the presence of circulating anticyclic citrullinated peptide antibodies appears to be associated with stronger evidence of subclinical atherosclerosis in RA.

Sherer Y, Shoenfeld Y. · Department of Medicine 'B' and of the Center for Autoimmune Diseases at Sheba Medical Center, Tel Hashomer, Israel. · Nat Clin Pract Rheumatol. · Pubmed #16932663 No free full text.

Abstract: Atherosclerosis is a pathologic process affecting blood vessels, which leads to the development of cardiovascular disease. The immune system is involved in atherogenesis and in the pathogenesis of atherosclerosis. Several autoimmune rheumatic conditions, including rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome, are characterized by enhanced atherosclerosis and consequently higher cardiovascular morbidity and mortality rates. Enhanced atherosclerosis, in these diseases, can manifest as overt cardiovascular diseases, but could be detected at an earlier stage by identification of abnormal endothelial function and arterial intima-media thickening. Both classical and nonclassical risk factors are presumed to contribute to atherosclerosis progression in rheumatic diseases. As atherosclerosis can be considered to be an immune-mediated process, several experimental strategies exist for its immunomodulation, including induction of immune tolerance. In this article, we briefly review the contribution of autoimmune elements, such as autoreactive lymphocytes and autoantibodies to atherosclerosis and discuss the nature of atherosclerosis in autoimmune rheumatic diseases.

Ram M, Sherer Y, Shoenfeld Y. · Department of Medicine B & Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Jerusalem, Israel. · J Clin Immunol. · Pubmed #16652230 No free full text.

Abstract: Matrix metalloproteinases (also named matrixin or MMPs) are a major group of enzymes that regulate cell-matrix composition by using zinc for their proteolytic activities. They are essential for various normal biological processes such as embryonic development, morphogenesis, reproduction tissue resorption, and remodeling. Metalloproteinases also play a role in pathological processes including inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer. Herein we review the involvement of MMP-9 in a variety of autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, rheumatoid arthritis, multiple sclerosis, polymyositis and atherosclerosis. MMP-9 plays either a primary or secondary role in each one of those autoimmune diseases by its up or down-regulation. It is not expressed constantly but rather is induced or suppressed by many regulating molecules. This feature of MMP-9 along with its involvement in disease pathogenesis turns it into a target for therapy of autoimmune diseases.

Shepshelovich D, Sherer Y, Shoenfeld Y. · Department of Medicine B & Center for Autoimmune Diseases, Sheba Medical Center Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel. · Harefuah. · Pubmed #16146154 No free full text.

Abstract: Cardiovascular manifestations are frequent in rheumatoid arthritis (RA) and significantly contribute to morbidity and mortality in this disorder. Premature atherosclerosis is responsible for these complications, as supported by autopsy studies. Moreover, a high prevalence of sub-clinical atherosclerosis--evaluated by imaging and instrumental parameters--has been reported. Traditional risk factors cannot completely account for accelerated atherosclerosis in RA. The presence of RA by itself and the immunosuppressive therapy (especially corticosteroids) represent non-traditional risk factors for premature atherosclerosis. Additional factors playing a synergistic role in the atherosclerotic process are systemic chronic inflammation frequently associated with RA and both humoral and cellular specific autoimmune responses. Herein we review and discuss atherosclerosis in rheumatoid arthritis, with special emphasis on clinical presentations, pathogenesis and therapy.

Zinger H, Sherer Y, Shoenfeld Y. · Department of Medicine B and Center of Autoimmune diseases, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Clin Rev Allergy Immunol. · Pubmed #18991025 No free full text.

Abstract: Atherosclerosis is one of the major entities leading to morbidity and mortality in the western world. It is known now that atherosclerosis cannot be explained merely by the presence of the Framingham traditional risk factors and that autoimmunity takes a significant role in its pathogenesis. It is also known that individuals with autoimmune diseases demonstrate increased incidence of cardiovascular manifestations and subclinical atherosclerotic disease. The mechanisms for the assumed accelerated atherosclerosis in diseases such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, and systemic sclerosis include the classical risk factors, but may also be due to chronic inflammatory processes and immune dysregulation. Autoantibodies, autoantigens, pro-inflammatory cytokines, and infectious agents play a role in that process. Involvement of autoimmunity in the pathogenesis of accelerated atherosclerosis in rheumatic diseases and the common pathway that leads to this condition may lead to significant change in prevention of treatment.

Barzilai O, Sherer Y, Ram M, Izhaky D, Anaya JM, Shoenfeld Y. · Center for Autoimmune Diseases, Department of Medicine B, Sheba Medical Center, Tel-Hashomer, Israel. · Ann N Y Acad Sci. · Pubmed #17894021 No free full text.

Abstract: To date, it is believed that the origin of autoimmune diseases is one of a multifactorial background. A genetic predisposition, an immune system malfunction or even backfire, hormonal regulation, and environmental factors all play important roles in the pathogenesis of autoimmune diseases. Among these environmental factors, the role of infection is known to be a major one. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are considered to be notorious as they are consistently associated with multiple autoimmune diseases. A cohort of 1595 serum samples, of 23 different autoimmune disease groups, was screened for evidence of prior infection with EBV and CMV. All samples were screened for antibodies against EBV nuclear antigen-1 (IgG), EBV viral capsid antigen (IgG and IgM), EBV early antigen (IgG), EBV heterophile antibody, and CMV (IgG and IgM) antibodies using Bio-Rad's BioPlex 2200. A new association is proposed between EBV and polymyositis, as results show a significant increase in titers of various EBV target analytes when compared with healthy controls. Our results also support prior information suggesting the association between EBV and multiple autoimmune diseases, including SLE, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, pemphigus vulgaris, giant cell arthritis, Wegener's granulomatosis, and polyarteritis nodosa (PAN). Elevated CMV IgG titers were observed in sera of SLE patients. Our data support the theory that EBV is notoriously associated with many autoimmune diseases. CMV appears to be associated to autoimmune diseases as well, yet establishing this theory requires further investigation.

Sherer Y, Gerli R, Bocci EB, Gilburd B, Vaudo G, Bistoni O, Shoenfeld Y. · Department of Medicine 'B' and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel. · Ann N Y Acad Sci. · Pubmed #17894004 No free full text.

Abstract: The aim of this study was to examine whether heat-shock protein (HSP)-65 autoantibodies are associated with early atherosclerosis in rheumatoid arthritis (RA). Intima-media thickness (IMT) was measured in the carotid arteries of 100 RA patients and 69 control subjects. The IMT was evaluated on both carotid arteries in the common carotid, bifurcation, and internal arteries. Every patient underwent anti-HSP-65 antibody evaluation. Anti-HSP-65 antibodies were not more prevalent among patients compared with controls. Among controls, patients having "positive" anti-HSP-65 tended to have increased carotid artery IMT compared with "negative" patients, whereas among RA patients the opposite association was noted, and positive patients had significantly decreased carotid bifurcation IMT than negative patients without elevated levels of anti-HSP-65. As opposed to the association with cardiovascular diseases and atherosclerosis of anti-HSPs in the general population, among RA patients anti-HSP-65 cannot be regarded as associated with early atherosclerosis.

Sherer Y, Gerli R, Gilburd B, Bartoloni Bocci E, Vaudo G, Mannarino E, Shoenfeld Y. · Department of Medicine B and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel. · Lupus. · Pubmed #17439932 No free full text.

Abstract: Antiphospholipid and anti-oxidized LDL (anti-oxLDL) antibodies are associated with thrombosis and atherosclerosis. Rheumatoid arthritis (RA) is characterized by excess atherosclerosis and cardiovascular diseases. Our aim was to determine whether antiphospholipid and anti-oxLDL antibodies are associated with early atherosclerotic changes in RA. The levels of IgG and IgM anticardiolipin, IgG and IgM anti-beta-2-glycoprotein-I and anti-oxLDL autoantibodies have been evaluated in 82 patients having RA. Carotid artery intima-media thickness (IMT) was measured in the carotid arteries in the common carotid, bifurcation and internal carotid arteries. Elevated levels of IgG anticardiolipin antibodies were detected in 17 of 82 (21%) RA patients, including 7 with medium-to-high levels considered being clinically relevant. These patients had significantly elevated mean carotid and carotid bifurcation IMT compared with RA patients without elevated anticardiolipin. No such association was found regarding other autoantibodies tested. Anticardiolipin antibodies are prevalent in RA and are associated with early atherosclerotic changes, supporting a rational for measuring them in RA, and upon detection treat the patients in order to decrease chances of atherosclerosis progression and thrombosis.

Shovman O, Sherer Y, Gilbourd B, Gerli R, Bocci EB, delle Monache F, Luccioli F, Shoenfeld Y. · Department of Medicine B and Center of Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel. · Isr Med Assoc J. · Pubmed #16382698 links to  free full text

Abstract: BACKGROUND: Heat shock proteins are highly conserved immunodominant antigens found in various species. Humoral immune responses to mycobacterial HSP65 and human HSP60 have been established in a number of human autoimmune diseases. OBJECTIVE: To assess the prevalence of antibodies to HSP60 kDa and HSP65 kDa in patients with Sjögren's syndrome as compared to normal subjects. METHODS: Thirty-seven patients with SS were compared with normal controls. The antibodies against human HSP60 were measured by the Anti-Human (IgG/IgM) HSP60 ELISA kit. IgGs and IgMs to mycobacterial HSP65 were determined using an enzyme-linked immunosorbent assay with mycobacterial recombinant HSP65 antigens. RESULTS: The levels of both anti-HSP60 and -HSP65 were lower in patients compared with controls. IgG autoantibodies to HSP60 were significantly different between groups: 162 +/- 55.1 ng/ml in controls versus 112.3 +/- 30.6 ng/ml in SS patients (P < 0.001). The levels among controls of anti-HSP65 IgM isotype were also significantly higher than among the SS patients: 111.6 +/- 33.4 U/ml versus 96.1 +/- 8.9 U/ml (P= 0.01). CONCLUSIONS: The results of the present study show that the levels of different isotypes of anti- HSP60 and HSP65 antibodies were lower in patients with SS than in normal subjects. Additional studies in larger patient populations are required to evaluate the prevalence of these autoantibodies in SS patients.

Shovman O, Gilburd B, Zandman-Goddard G, Sherer Y, Orbach H, Gerli R, Shoenfeld Y. · Center for Autoimmune Diseases, Department of Medicine B, Sheba Medical Center, Israel. · Clin Dev Immunol. · Pubmed #16295525 links to  free full text

Abstract: OBJECTIVE: To compare the diagnostic utility of laboratory variables, including matrix metalloproteinase-3 (MMP-3), anticyclic citrullinated peptide (CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in patients with erosive and non-erosive rheumatoid arthritis (RA). METHODS: We assembled a training set, consisting of 60 patients with RA, all fulfilling the revised criteria of the American College of Rheumatology. A commercial enzyme linked immunosorbent assay (ELISA) was used both to test for anti-CCP antibodies (second generation ELISA kit) and MMP; RF were detected by latex-enhanced immunonephelometric assay. CRP was measured by latex turbidimetric immunoassay. RESULTS: The levels of anti-CCP antibody titers and ESR were significantly higher in patients with erosive disease than those in non-erosive RA patients (p < 0.001 and 0.0341) respectively. Moreover, a higher frequency of elevated titers of anti-CCP antibodies was found in RA patients with erosions compared to patients with non-erosive RA (78.3% vs. 43.2% respectively). The ROC curves of anti-CCP passed closer to the upper left corner than those other markers and area under the curve (AUC) of anti-CCP was significantly larger than AUC of other markers (0.755 for anti-CCP, 0.660 for ESR, 0.611 for CRP, 0.577 for RF, and 0.484 for MMP-3 female). A positive predictive value was higher for anti-CCP antibodies in comparison to other markers. We did not find significant statistical correlation between anti-CCP antibody titers and inflammatory markers such as ESR or CRP. However, we confirmed the correlation of elevated titers of anti-CCP antibodies and RF in both groups of patients whereas the degree of correlation was more significant in non-erosive patients. CONCLUSION: The results of our study suggest that the presence of elevated anti-CCP antibody titers have better diagnostic performance than MMP-3, RF, CRP and ESR in patients with erosive RA.

Sherer Y, Gerli R, Vaudo G, Schillaci G, Gilburd B, Giordano A, Bocci EB, Allegrucci R, Marchesi S, Mannarino E, Shoenfeld Y. · Department of Medicine B and Center of Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 52621, Israel. · Ann N Y Acad Sci. · Pubmed #16126971 No free full text.

Abstract: Antiphospholipid antibodies characterize the antiphospholipid syndrome (APS), but they can also be found in various autoimmune, infectious, and malignant conditions. This study's objectives were to detect the prevalence of antiphospholipid and antioxidized low-density lipoprotein (anti-oxLDL) antibodies among patients with rheumatoid arthritis (RA) who did not have clinical manifestations of APS. Using a standard enzyme-linked immunosorbent assay (ELISA), we evaluated the levels of immunoglobulin G (IgG) and IgM anticardiolipin, IgG, and IgM anti-beta-2-glycoprotein-I (anti-beta(2)GPI), and anti-oxLDL autoantibodies in 82 patients with RA. The cutoff levels for detecting these autoantibodies were 15 IgG phospholipid units (GPL), 15 IgM phospholipid units (MPL), and 25 ELISA units (EU)/mL, respectively. Elevated levels of IgG anticardiolipin antibodies were detected in 17 of 82 (21%) RA patients, including 10 with low levels of IgG anticardiolipin and 7 with medium to high levels of anticardiolipin autoantibodies. IgM anticardiolipin was found in only 1 (1%) patient, and both IgG and IgM anti-beta(2)GPI were found in 3 (4%) patients with RA. Elevated levels of anti-oxLDL antibodies were found in 8 (10%) patients, 4 of whom also had elevated levels of IgG anticardiolipin. We conclude that IgG anticardiolipin autoantibodies can be found in about one-fifth of RA patients who do not have clinical manifestations of APS. Whether the presence of anticardiolipin signifies increased risk for thrombosis and atherosclerosis in these patients should be studied further.

Gerli R, Sherer Y, Vaudo G, Schillaci G, Gilburd B, Giordano A, Bocci EB, Allegrucci R, Marchesi S, Mannarino E, Shoenfeld Y. · Section of Internal Medicine and Oncological Sciences, Center for the Study of Rheumatic Diseases, University of Perugia, Perugia, Italy. · Ann N Y Acad Sci. · Pubmed #16126969 No free full text.

Abstract: This study was designed to compare intima media thickness (IMT) of the carotid arteries among rheumatoid arthritis (RA) patients and controls and to determine whether disease-associated characteristics, smoking, and other classic risk factors for atherosclerosis are associated with IMT values. IMT was measured in the carotid arteries of 101 RA patients and 75 control subjects. The IMT was evaluated in the common carotid (CC), carotid bifurcation (BI), and internal carotid (IC). Eight IMT values were calculated including four mean and four maximal values of CC, BI, IC, and carotid artery (C). The following data were obtained for every patient: age, sex, body mass index (BMI), presence of erosions, extra-articular manifestations, rheumatoid factor, medications, hypertension, hypercholesterolemia, diabetes mellitus, smoking status, daily number of cigarettes, number of smoking years, family history of cardiovascular diseases (CVD), and erythrocyte sedimentation rate (ESR) levels. RA patients had significantly higher mean-BI IMT than controls (1.02 mm vs. 0.89 mm; P < 0.01), higher incidence of increased mean-BI IMT and max-BI IMT, but lower incidence of increased max-IC IMT than controls. Factors significantly associated with IMT in the controls were age, BMI, and hypertension, whereas factors significantly associated with IMT in RA patients were age and smoking status. Mean carotid IMT was associated with all characteristics related to smoking in RA patients. Current smokers had higher mean carotid IMT and internal carotid artery IMT than former smokers. RA is associated with higher carotid artery bifurcation IMT. The profile of factors associated with IMT values is different between RA patients and controls. Smoking is an important factor augmenting early atherosclerosis in RA patients.

Levy Y, Uziel Y, Zandman GG, Amital H, Sherer Y, Langevitz P, Goldman B, Shoenfeld Y. · Department of Medicine B and the Centre for Autoimmune Diseases, Sheba Medical Centre Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel. · Ann Rheum Dis. · Pubmed #14644864 links to  free full text

Abstract: BACKGROUND: Peripheral neuropathy is a prominent feature of the systemic and secondary vasculitides. Usually, it is responsive to corticosteroids, but in certain cases it may be resistant to corticosteroid or immunosuppressive treatment, or both. OBJECTIVE: To present patients who exhibited various inflammatory diseases accompanied with vasculitic peripheral neuropathies for which intravenous immunoglobulin (IVIg) was used for treatment. METHODS: Six patients with Sjögren's syndrome, systemic lupus erythematosus (SLE), vaccination induced vasculitis, Churg-Strauss vasculitis, mixed cryoglobulinaemia associated with hepatitis C infection, or sarcoidosis were included. All developed vasculitic peripheral neuropathy, and were treated with high dose IVIg (2 g/kg body weight). The patients were followed up for 1-5 years after this treatment. RESULTS: In four patients (Sjögren's syndrome, Churg-Strauss vasculitis, SLE, and vaccination induced vasculitis) the neuropathy resolved after IVIg treatment. CONCLUSION: IVIg may be beneficial in cases of resistant vasculitic peripheral neuropathy. IVIg should probably be considered as a sole or adjuvant treatment for patients with contraindications to conventional treatment, or alternatively, for patients in whom conventional treatment has failed.

Sherer Y. · Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel. · Isr Med Assoc J. · Pubmed #18432028 links to  free full text

This publication has no abstract.

Gerli R, Bartoloni Bocci E, Sherer Y, Vaudo G, Moscatelli S, Shoenfeld Y. · No affiliation provided · Ann Rheum Dis. · Pubmed #18408112 No free full text.

This publication has no abstract.