Rheumatoid Arthritis: Shoenfeld Y

Nussinovitch U, Shoenfeld Y. · Center of Autoimmune Diseases, Depatment of Medicine "B", Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Harefuah. · Pubmed #17674550 No free full text.

Abstract: Cachexia is a common finding in various diseases such as chronic renal failure, HIV infection, malignancies, chronic obstructive pulmonary disease, congestive heart failure and rheumatoid arthritis. It is estimated that 30% of patients with malignancies will appear with cachexia, and up to 80% of patients with progressive metastatic disease will be affected. Cachexia is associated with decreased overall survival rates, and decreased beneficial effects of chemotherapy treatment. The underlying pathological processes in cachexia are not completely understood. It is believed that tumor necrosis factor alpha (TNFalpha) plays an essential rule in cachexia induction and propagation. This article reviews and discusses current anti-cachexia treatments, with special emphasis on anti-TNF-alpha treatment in malignancies and various other diseases.

Orbach H, Shoenfeld Y. · No affiliation provided · Harefuah. · Pubmed #12696470 No free full text.

Abstract: Early diagnosis of rheumatoid arthritis (RA) is important since aggressive therapy should begin at an early stage. Diagnosis is made on a clinical basis, supported by the determination of rheumatoid factor (RF). However, RF is also positive in healthy subjects, as well as in other autoimmune and infectious diseases. Two other diagnostic markers with a high specificity for RA, antiperinuclear factor (APF) and antikeratin antibodies (AKA), are not in general use because of technical difficulties. APF and AKA are antifilaggrin antibodies (AFA) that bind to determinants rich in the unusual amino acid citrulline, generated by posttranscriptional modification of arginine residues by the enzyme peptidylarginine deiminase (PAD). Enzymatic determination of recombinant filaggrin fragments produces linear peptides, which are recognized by RA-specific autoantibodies. After substitution of serine by cysteine, a cyclic peptide is formed. The conformational change mimics the original structure of the filaggrin and enhances the affinity of the antibodies. Recently, an anti-cyclic citrullinated peptide (anti-CCP) ELISA was developed. The sensitivity of this test is usually 51%-68%, with a specificity of about 96%-98% (significantly higher than that of RF). Together with RF, anti-CCP increases the ability to diagnose patients with early RA. The test might help to predict which patients will develop persistent disease with evidence of radiologic lesions. Implementation of the highly specific anti-CCP test in conjunction with RF would enable reliable early diagnosis in some cases and allow the initiation of aggressive therapy with disease modifying anti-rheumatic drugs (DMARDs).

Shovman O, Shoenfeld Y. · No affiliation provided · Harefuah. · Pubmed #10979406 No free full text.

This publication has no abstract.

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.

Szekanecz Z, Kerekes G, Dér H, Sándor Z, Szabó Z, Végvári A, Simkovics E, Soós L, Szentpétery A, Besenyei T, Szücs G, Szántó S, Tamási L, Szegedi G, Shoenfeld Y, Soltész P. · Division of Rheumatology, Third Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary. · Ann N Y Acad Sci. · Pubmed #17893998 No free full text.

Abstract: Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. Both traditional, Framingham risk factors and inflammation-associated factors are involved in RA-associated atherosclerosis. Among imaging techniques, the early determination of common carotid intima-media thickness (ccIMT), flow-mediated vasodilation (FMD), and nitroglycerine-mediated vasodilation (NMD) may be useful to determine atherosclerosis and endothelial dysfunction. We and others found increased ccIMT and impaired FMD in RA patients. Among immunological and metabolic laboratory markers, anticyclic citrullinated peptide (anti-CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), Th0/Th1 T cells, homocysteine, dyslipidemia, decreased folate and vitamin B12 production, and impaired paraoxonase activity may all be involved in the development of vascular disease in RA. The early diagnosis of endothelial dysfunction and atherosclerosis, active immunosuppressive treatment, the use of drugs that control atherosclerosis, changes in sedentary lifestyle, and the close follow-up of RA patients may help to minimize cardiovascular risk in these individuals.

Orbach H, Shoenfeld Y. · Department of Medicine B, Wolfson Medical Center, Holon, Israel. · Autoimmun Rev. · Pubmed #17854745 No free full text.

Abstract: The autoimmune diseases are more common in females. The sex hormones have an important role in this gender bias, mainly estrogen and prolactin (PRL) which modulate the immune response. PRL is secreted from the pituitary gland and other organs and cells mainly the lymphocytes. PRL has an immunostimulatory effect and promotes autoimmunity: PRL impairs the negative selection of autoreactive B lymphocytes occurring during B cell maturation into fully functional B cells. PRL has an anti-apoptotic effect, enhances proliferative response to antigens and mitogens and enhances the production of immunoglobulins and autoantibodies. Hyperprolactinemia (HPRL) is observed in multi-organ and organ specific autoimmune diseases like systemic lupus erythematosus (SLE) rheumatoid arthritis (RA), Sjogren's syndrome (SS), Hashimoto's thyroiditis (HT) and multiple sclerosis (MS). There is no consistent correlation between PRL levels and disease activity. Murine models and small studies in SLE patients suggest some role of dopamine agonists in the therapy of those diseases. The genetic factor may have a role in humans as in animal models. The PRL isoform has an important effect on the bioactivity on prolactin receptors (PRL-Rs).

Arnson Y, Amital H, Shoenfeld Y. · Department of Medicine D, Meir Medical Center, Kfar-Saba, affiliated to Tel-Aviv University Sackler Faculty of Medicine, Israel. · Ann Rheum Dis. · Pubmed #17557889 No free full text.

Abstract: Vitamin D is frequently prescribed by rheumatologists to prevent and treat osteoporosis. Several observations have shown that vitamin D inhibits proinflammatory processes by suppressing the enhanced activity of immune cells that take part in the autoimmune reaction. Moreover, recent evidence strongly suggests that vitamin D supplementation may be therapeutically beneficial, particularly for Th1-mediated autoimmune disorders. Some reports imply that vitamin D may even be preventive in certain disorders such as multiple sclerosis and diabetes type 1. It seems that vitamin D has crossed the boundaries of calcium metabolism and has become a significant factor in a number of physiological functions, specifically as a biological inhibitor of inflammatory hyperactivity.

Carvalho JF, Blank M, Shoenfeld Y. · Rheumatology Division, São Paulo University, School of Medicine, São Paulo, Brazil. · J Clin Immunol. · Pubmed #17340192 No free full text.

Abstract: Vascular endothelial growth factor (VEGF) is a potent stimulating factor for angiogenesis and vascular permeability. There are eight isoforms with different and sometimes overlapping functions. The mechanisms of action are under investigation with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins, which were not previously associated to angiogenesis. VEGF has important physiological actions on embryonic development, healing, and menstrual cycle. It also has a great role in pathological conditions that are associated to autoimmune diseases. There is considerable evidence in various autoimmune diseases such as in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis of an interrelationship between the VEGF system and theses disorders. Serum levels of VEGF correlate with disease activity in a large number of autoimmune diseases and fall with the use of standard therapy. We raised the possible future therapeutic strategies in autoimmune diseases with the anti-VEGF or anti-VEGFR (receptor). So far, this therapy has been used in cancer and macular ocular degeneration in diabetes. This review outlines the evidence for VEGF participation in various autoimmune diseases and proposes lines for future research in this field.

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.

Harel M, Shoenfeld Y. · Center for Autoimmune Diseases, Department of Medicine B, Sheba Medical Center, Tel-Aviv University, Tel-Hashomer 52621, Israel. · Ann N Y Acad Sci. · Pubmed #16855160 No free full text.

Abstract: Many autoimmune diseases are chronic conditions that progress over the course of years, and are characterized by the presence of autoantibodies that precede the overt disease by months or years. As examples, the presence of two islet cell antibodies (ICA) are associated with a 50% risk of developing diabetes mellitus in 5 years, anticyclic citrullinated (anti-CCP) antibodies are found in the sera of rheumatoid arthritis (RA) patients a median of 4.5 years before the overt disease, and in systemic lupus erythematosus (SLE), patients accrue antibodies throughout a foreseen course during the 3-4 years prior to the clinical symptoms. This ability to predict autoimmune diseases, or rather their clinical manifestations, leads to the prospect of screening healthy individuals for autoantibodies. The importance of such a notion lies not only in the ability to prevent life-threatening manifestations, such as Addisonian's crisis and thyroid storm, but also in the ability to treat and even prevent overt autoimmune diseases. Among such documented treatment modalities are administration of aspirin in antiphospholipid syndrome, ursodeoxycholic acid in primary biliary cirrhosis (PBC), vitamin D in SLE and autoimmune thyroid diseases (AITD), and more. Although additional studies are still needed to fully assess these notions, as well as the appropriate screening strategies to apply them, one cannot ignore the prospect of predicting and preventing autoimmunity.

Borchers AT, Selmi C, Cheema G, Keen CL, Shoenfeld Y, Gershwin ME. · Department of Nutrition, USA. · Autoimmun Rev. · Pubmed #16697970 No free full text.

Abstract: One of the most enigmatic problems in rheumatology has been juvenile idiopathic arthritis (JIA). Firstly, the classification has often depended on clinical features that have variations between patients. Secondly, there are different classification schemes in usage and there are few objective serologic tests that help to resolve the differences between the criteria sets. Thirdly, only recently have significant advances been made in understanding the immunology and immunopathology of JIA and, in particular, new treatment options. In this review, we will define the historical basis of JIA and emphasize not only the clinical features, but also the immunological characteristics, the pathogenesis, and treatment options. We will also discuss, in particular, quality of life, psychosocial functioning, socioeconomic outcomes and the difficult area of mortality. Finally, this review will attempt to bridge genetic observations with clinical presentation. JIA represents a relatively common syndrome of pediatric onset rheumatologic disease and a better understanding of the clinical definition, the relationship to autoimmunity, and novel treatments with biologic agents are critical for improved patient care.

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.

Sarzi-Puttini P, Atzeni F, Shoenfeld Y, Ferraccioli G. · Rheumatology Unit, University Hospital L. Sacco, Via GB Grassi 74, 20157 Milan, Italy. · Autoimmun Rev. · Pubmed #15823501 No free full text.

Abstract: Cardiovascular disease (CVD) is responsible for 35-50% of rheumatoid arthritis (RA) deaths, whereas, in the general UK adult population, coronary heart disease is responsible for 1/4 deaths in males and 1/5 deaths in female. This increased risk may be attributable to RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia or vascular inflammation, or to morbidity related to medications and high levels of tumor necrosis factor-alpha (TNF-alpha). The possible roles of TNF-alpha in the development of atherosclerosis include the recruitment of inflammatory cells to the site of injury or the promotion of adverse vascular smooth muscle cell remodelling. TNF-alpha may also act as a proinflammatory factor in plaque rupture. Anticytokine therapy could prove beneficial in the treatment of patients with heart failure. While early studies supported this hypothesis, anti-TNF strategies have not demonstrated salutary benefits in large multicenter randomized and placebo-controlled clinical trials in patients with symptomatic heart failure. There is a variety of possible explanations for the failure of anti-TNF therapy: (1) TNF antagonism has untoward effects in the setting of heart failure; (2) the biological agents used in the trials were intrinsically toxic; (3) sex and race may have important implications in the outcome after anticytokine therapy; (4) the TNF-alpha protein contains a polymorphism, and, in fact, genoma plays a role in modifying the pharmacologic response to anticytokines; (5) anti-TNF-alpha approaches could have had pharmacodynamic interactions with other heart failure medications; and (6) the patients in these trials may have been inappropriately selected. These disappointing results may determine controversial attitude in the long-term treatment with anti-TNF agents in RA or Crohn's disease. The effects of TNF-alpha blockers on incident cases of congestive heart failure (CHF) in RA are controversial. The available published data suggest the following: (a) RA patients with history of CHF and a concomitant indication for the use of TNF-alpha blockers do not need a baseline cardiac evaluation to screen for heart failure; (b) patients with well-compensated mild CHF New York Heart Association (NYHA) classes I and II and a concomitant indication for the use of TNF-alpha blockers should be evaluated at baseline and then be closely monitored for any clinical signs of worsening heart failure; and (c) patients with (NYHA) class III or IV heart failure should not be treated with TNF-alpha blockers in any case.

Toubi E, Shoenfeld Y. · Divison of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel. · Autoimmunity. · Pubmed #15621572 No free full text.

Abstract: Many tissue injuries and immune mediated pathologies such as graft allo-rejections were found to involve CD40-CD40 ligand (CD40L, CD154) signaling pathway. The disruption of this pathway in many animal models led to the improvement of graft survival in these models. CD40-CD154 interactions were also shown to play a significant role in the maintenance of autoimmunity, and the production of auto-antibodies in systemic lupus erythematosus (SLE). High-level expression of CD154 has been detected on T cells from patients with active SLE, rheumatoid arthritis (RA) and other autoimmune diseases, indicating that such cells could account for the high-level expression of immune accessory molecules on B cells of patients with active disease. An increased serum level of soluble CD154 was also reported in SLE, RA, and Sjogren's disease in correlation with the relevant auto-antibodies and with the clinical disease activity. Anti-CD154 antibody therapy prevents auto-antibody production and renal immune complex deposition in lupus nephritis, indicating that disruption of this pathway could be a beneficial treatment in SLE. However, the etiology of the higher than expected number of thromboembolic events in anti-CD154 treated SLE patients should be investigated and preventive measures should be considered.

Abu-Shakra M, Buskila D, Shoenfeld Y. · Autoimmune Rheumatic Diseases Unit and Departments of Medicine B & D, Soroka Medical Center, Beer-Sheva, Israel. · Clin Rev Allergy Immunol. · Pubmed #12794257 No free full text.

Abstract: Osteonecrosis is a clinical entity characterized by death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone (1,2). Other aspects of this condition include avascular necrosis, aseptic necrosis, and osseous ischemic necrosis of bones. Osteonecrosis is classified into two main forms; post-traumatic and nontraumatic. The post-traumatic form of osteonecrosis usually develops as a result of traumatic displacement of bone fragments, which leads to impaired blood supply and ischemia to the affected bone. Osteonecrosis of the femoral head is common following fracture of the femoral neck. A variety of systemic diseases and clinical conditions are associated with nontraumatic osteonecrosis. These include autoimmune rheumatic diseases, alcoholism, pregnancy, Gaucher's disease, thrombophilia, corticosteroid therapy, Sickle-cell anemia, pancreatitis, inflammatory bowel diseases, and use of cytotoxic drugs and others. Idiopathic forms of osteonecrosis have also been reported (2-4). Among the rheumatic diseases, osteonecrosis is strongly associated with systemic lupus erythematosus (SLE) (5). However, osteonecrosis has been diagnosed in patients with primary antiphospholipid syndrome (APS) (6), rheumatoid arthritis (7), and systemic vasculitis (8). This article reviews the causes, clinical and epidemiological features, diagnosis, and treatment options for osteonecrosis among patients with SLE.

Lev S, Shoenfeld Y. · No affiliation provided · Harefuah. · Pubmed #11851095 No free full text.

This publication has no abstract.

Ehrenfeld M, Abu-Shakra M, Buskila D, Shoenfeld Y. · Research Centre for Autoimmune Diseases, Sheba Medical Centre, Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel. · Blood Cells Mol Dis. · Pubmed #11778659 No free full text.

Abstract: Autoimmune rheumatic diseases and lymphocytic malignancies are related and this association is bidirectional. Lymphomas occur more frequently in the course of autoimmune disease and autoimmune rheumatic manifestations occur in the course of lymphocytic malignancies. An increased incidence of malignant lymphocytic diseases is present in patients with rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and autoimmune thyroid disease. Descriptions of lymphocytic malignancies among other autoimmune rheumatic disease have been published. In some patients, the malignant disease is diagnosed months or years before the appearance of the rheumatic disease.

Gorshtein A, Shoenfeld Y. · Autoimmune Disease Research Unit, Department of Internal Medicine B, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University. · Harefuah. · Pubmed #11759380 No free full text.

Abstract: Pemphigus is an autoimmune blistering disease of skin and mucous membranes. The classic types of pemphigus are pemphigus vulgaris and pemphigus foliaceus. In this review we summarize recent advancement in the etiology and the pathogenesis of pemphigus. Desmogleins--transmembrane glycoproteins involved in intracellular adhesion--were recognized as targets of pemphigus antibodies. It was found that the distribution and the expression of desmogleins can explain the difference in the localization of lesions in pemphigus vulgaris and pemphigus foliaceus. Pemphigus develops in a two-step process. The first step leads to the presence of a low titer of autoantibody, the second step results in a significant increase in the antibody titer which causes the clinical stage of the disease. Selective presentation of self peptides can explain the Major Histocompatibility Complex (MHC)--linked susceptibility to autoimmune diseases including pemphigus and rheumatoid arthritis. Peptides selective for the disease-associated molecules can be identified and used to search for microbiologic factors that can take part in the pathogenesis of pemphigus.

Ehrenfeld M, Langevitz P, Shoenfeld Y. · No affiliation provided · Harefuah. · Pubmed #10959300 No free full text.

This publication has no abstract.

Lorber M, Shoenfeld Y. · Institute of Clinical Immunology and Allergy, Rambam Medical Center, B. Rappaport Faculty of Medicine, Technion, Haifa, Israel. · Clin Rev Allergy Immunol. · Pubmed #10907107 No free full text.

This publication has no abstract.

Krause I, Blank M, Shoenfeld Y. · Research Unit of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel. · Crit Rev Immunol. · Pubmed #10770268 No free full text.

Abstract: The concept of oral tolerance refers to a form of peripheral tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered nonfunctional or hyporesponsive by prior oral administration of an antigen. The primary mechanisms mediating oral tolerance include deletion, anergy of antigen-specific T cells and active cellular suppression, the primary determining factor being the dose of fed antigen. Low doses favor active suppression, whereas high doses favor deletion and anergy. Active cellular suppression is mediated by the induction of regulatory T cells in the gut-associated lymphoid tissue, which migrate to the systemic immune system. One of the primary mechanisms of active cellular suppression is via secretion of suppressive cytokines such as TGF-beta, IL-4, and IL-10 following antigen-specific triggering. TGF-beta is produced both by CD4+ and CD8+ GALT-derived T cells and is an important mediator of the active suppression component of oral tolerance. CD4+ cells that primarily produce TGF-beta appear to be a unique T-cell subset and termed Th3 cells. Oral tolerance was successfully studied in a variety of experimental models for autoimmune diseases, among them experimental autoimmune encephalomyelitis, experimental arthritis, experimental anti-phospholipid syndrome, experimental autoimmune uveoretinitis, experimental insulin dependent diabetes mellitus (IDDM), and experimental autoimmune myasthenia gravis. The results obtained in experimental animal models have led to the conduction of several clinical trials of oral tolerance in patients with multiple sclerosis, rheumatoid arthritis, uveitis, and IDDM. Conflicting results were obtained, and although some improvement has been noted in some of the patients, broad ranging clinical improvement has not yet been observed. A more accurate choice of antigens, as well as more precise dosing and timing of antigen-administration might lead to better results in the future.

Shoenfeld Y, Aron-Maor A. · Department of Internal Medicine B, Sheba Medical Center, Tel Hashomer, Israel. · J Autoimmun. · Pubmed #10648110 No free full text.

Abstract: The question of a connection between vaccination and autoimmune illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as measles and anti-hepatitis B virus (HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other autoimmune illnesses have been associated with vaccinations. Tetanus toxoid, influenza vaccines, polio vaccine, and others, have been related to phenomena ranging from autoantibodies production to full-blown illness (such as rheumatoid arthritis (RA)). Conflicting data exists regarding also the connection between autism and vaccination with measles vaccine.So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and autoimmune findings has been examined: in healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed.Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome).The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive).

Kerekes G, Soltész P, Dér H, Veres K, Szabó Z, Végvári A, Szegedi G, Shoenfeld Y, Szekanecz Z. · Cardiovascular Unit, Third Department of Medicine, University of Debrecen Medical and Health Science Center, Móricz Zs krt. 22., 4032, Debrecen, Hungary. · Clin Rheumatol. · Pubmed #19319624 No free full text.

Abstract: Increased cardiovascular mortality has been associated with rheumatoid arthritis (RA). There have been reports indicating that tumor necrosis factor blockers may exert favorable but transient effects on lipid profile, flow-mediated vasodilation (FMD) of the brachial artery, and common carotid intima-media thickness (ccIMT) in RA. In this study, we assessed the effects of rituximab on FMD, ccIMT, and lipid profile. Five female RA patients received two infusions of 1000 mg rituximab i.v. High-resolution B-mode ultrasound was used to assess brachial FMD and ccIMT. We also determined plasma total cholesterol (TC), HDL-C, LDL-C, and triglyceride (Tg) levels. Assessments were performed at baseline, as well as at weeks 2, 6, and 16 after the first infusion. Rituximab (RTX) treatment resulted in a rapid and sustained improvement in FMD. The mean improvement was 30%, 22%, and 81% at weeks 2, 6, and 16, respectively. RTX had little effect on atherosclerosis within this short period of time; however, we observed 10%, 9%, and 2% decreases in ccIMT at weeks 2, 6, and 16, respectively. RTX therapy resulted in 3-11% decrease in TC, as well as 14-35% increase in HDL-C levels. Two infusions of RTX exerted early and sustained favorable effects on endothelial dysfunction, as well as plasma TC and HDL-C levels. RTX may also decrease ccIMT; however, longer follow-up is needed to assess the prolonged effects of RTX on vascular function and lipid profile in RA patients.