Howard Amital

Effects of tobacco smoke on immunity, inflammation and autoimmunity.

Smoking is a central factor in many pathological conditions. Its role in neoplasm, lung and cardiovascular diseases has been well established for years. However it is less acknowledged the cigarette smoking affects both the innate and adoptive immune arms. Cigarette smoke was shown to augment the production of numerous pro-inflammatory cytokines such as TNF-alpha, IL-1, IL-6, IL-8 GM-CSF and to decrease the levels of anti-inflammatory cytokines such as IL-10. Tobacco smoke via multiple mechanisms leads to elevated IgE concentrations and to the subsequent development of atopic diseases and asthma. Cigarette smoke has also been shown activate in many ways macrophage and dendritic cell activity. While it is better evident how cigarette smoke evokes airway diseases more mechanisms are being revealed linking this social hazard to autoimmune disorders, for instance via the production of antibodies recognizing citrullinated proteins in rheumatoid arthritis or by the elevation of anti-dsDNA titers in systemic lupus erythematosus. The current review underlines the importance of smoking prevention and eradication not only in respiratory disorders but also in autoimmune conditions as well.

Vitamin D and autoimmunity: new aetiological and therapeutic considerations

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.

Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D?

Background Low serum vitamin D concentrations have been reported in several autoimmune disorders. Objective To assess whether low serum vitamin D concentrations are related to disease activity of patients with systemic lupus erythematosus (SLE). Methods 378 patients from several European and Israeli cohorts were pooled and their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. In order to combine the two systems the scores were converted into standardised values (z-scores), enabling univariate summary statistics for the two variables (SLEDAI-2K and ECLAM). The commercial kit, LIAISON 25-OH vitamin D assay (310900-Diasorin) was used to measure serum concentration of 25-OH vitamin D in 378 patients with SLE. Results A significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (Pearsons correlation coefficient r=−0.12, p=0.018). Conclusions In a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.

Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY)

Objective In patients with active rheumatoid arthritis (RA) despite methotrexate, to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy. Methods Double-blind, 2-year study in which adults with active RA (DAS28 >4.4) despite methotrexate were randomly assigned either to continue methotrexate with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO). The primary endpoint was the DAS28–erythrocyte sedimentation rate (ESR) remission rate at week 24. Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage. Results Of 556 randomly assigned patients, 512 (92%) completed 24 weeks. DAS28–ESR remission rates were 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8% (TCZ+MTX) and 70.3%/40.2%/25.4%/5.1% (TCZ+PBO; differences not significant). A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%). Radiographic progression was small and not different between groups (Genant–Sharp score progression ≤ smallest detectable change in 91% (TCZ+MTX) and 87% (TCZ+PBO)). Rates per 100 patient-years of serious adverse events and serious infections were 21 and six, respectively, for TCZ+MTX and 18 and six, respectively, for TCZ+PBO. Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO patients, respectively. Conclusion No clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed. The combination was more commonly associated with transaminase increases. Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients.

Novel biomarkers in autoimmune diseases : Prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases

Abstract:  The development of autoimmune diseases may be influenced by hormonal, immunomodulatory, and metabolic pathways. Prolactin (PRL), ferritin, vitamin D, and the tumor marker tissue polypeptide antigen (TPA) were measured in autoimmune diseases: systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis (PM), dermatomyositis (DM), multiple sclerosis (MS), autoimmune thyroid diseases, and antiphospholipid syndrome. Hyperprolactinemia (HPRL) was detected in 24% of PM patients, in 21% of SLE patients, in 6.7% of MS patients, 6% of RA patients, and in 3% of SSc patients. Hyperferritinemia was detected in 23% of SLE patients, 15% of DM patients, 8% of MS patients, and 4% of RA patients. The patients had relatively low levels of 25 OH Vitamin D: the average results (mean ± SD) were between 9.3 ± 4.4 to 13.7 ± 7.1 ng/mL in the different diseases, while the 25 OH Vitamin D concentrations less than 20 ng/mL are regarded as deficient. TPA levels were in the same range of the controls, elevated only in SLE. HPRL, hyperferritinemia, hypovitaminosis D, and TPA levels did not correlate with SLE activity elevated levels of rheumatoid factor or anti‐CCP antibodies in RA. HPRL, hyperferritinemia, and hypovitaminosis D have different immunological implications in the pathogenesis of the autoimmune diseases. Preventive treatment with vitamin D or therapy for HPRL with dopamine agonists, may be considered in certain cases. Hyperferritinemia may be used as an acute‐phase reactant marker in autoimmune diseases mainly SLE. TPA may be used to indicate the tendency for malignancies.

The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease

Melanin has several physiological roles in maintaining health, but, notably, it affects the synthesis of vitamin D. Melanin is the primary determinant of the degree of skin pigmentation and protects the body from harmful ultraviolet radiation. Synthesis of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) in the skin, however, is dependent on ultraviolet B light. Highly pigmented skin, to the level found in people of African origin, abrogates almost all ultraviolet-induced 1,25(OH)2D3 synthesis. Numerous animal models and clinical studies have underlined the essential role of vitamin D as a modulator of the different processes of the immune system. Evidence indicates that serum concentrations of 1,25(OH)2D3 and the prevalence of autoimmune diseases in a certain population are associated with the latitude at which that population resides. This article explores the relationship between skin pigmentation, vitamin D and the prevalence of autoimmune disease.

Anti-TNF therapy: Safety aspects of taking the risk

Rheumatoid arthritis (RA) therapy has been revolutionized in recent years following the introduction of three main anti-tumor necrosis factor-alpha inhibitors (anti-TNF) agents, infliximab, adalimumab and etanercept. Evidence in the literature indicates that patients treated with anti-TNF agents are at increased risk for bacterial infections, but it is not clear if this is a result of the treatment or of disease severity. The treatment has been recognized as a clear risk factor for reactivation of latent TB infections. So far, observational studies have not indicated any increased overall risk of cancer in RA patients treated with anti-TNF. The overall risk of lymphoma in these patients does not appear to differ greatly from that recorded among untreated patients, but rather is associated with the degree of disease activity rather than the type of therapy. There is a consensus in the literature that the likelihood of drug survival with infliximab is inferior to both adalimumab and etanercept, mostly due to increased risk of infection or allergic reactions. Due to the lack of head to head studies, there is no agreement as to which agent has the highest rates of treatment response and disease remission.

Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression

Background and aims Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterised by thrombosis, obstetric complications and the presence of anti-phospholipid antibodies such as anti-β2GPI-Abs. These antibodies may set off the coagulation cascade via several mechanisms, including the induction of tissue factor (TF) expression. Vitamin D has recently emerged as an immunomodulator that might exert an anti-thrombotic effect. Therefore, we studied serum vitamin D levels in a cohort of APS patients, as well as the effect of vitamin D in an in vitro model of APS-mediated thrombosis. Methods Serum vitamin D levels were measured in 179 European APS patients and 141 healthy controls using the LIAISON chemiluminescent immunoassay, and the levels were evaluated in conjunction with a wide spectrum of clinical manifestations. In an vitro model, anti-β2GPI antibodies were purified from four patients with APS to evaluate the expression of TF in activated starved human umbilical vein endothelial cells. The effect of vitamin D (1,25-dihydroxyvitamin D, 10 nm) on anti-β2GPI-Abs mediated TF expression was analysed by immunoblot. Results Vitamin D deficiency (serum level ≤15 ng/ml) was documented in 49.5% of our APS patients versus 30% of controls (p<0.001) and was significantly correlated with thrombosis (58% vs 42%; p<0.05), neurological and ophthalmic manifestations, pulmonary hypertension, livedo reticularis and skin ulcerations. In vitro vitamin D inhibited the expression of TF induced by anti-β2GPI-antibodies. Conclusions Vitamin D deficiency is common among APS patients and is associated with clinically defined thrombotic events. Vitamin D inhibits anti-β2GPI-mediated TF expression in vitro. Thus, vitamin D deficiency might be associated with decreased inhibition of TF expression and increased coagulation in APS. Evaluation of vitamin D status and vitamin D supplementation in APS patients should be considered.

Infectious associations of Celiac disease.

Infectious agents have been implicated in the pathogenesis of many autoimmune diseases. Celiac disease (CD) is an autoimmune disorder affecting patients with a specific genetic predisposition (HLA-DQ2, HLA-DQ8) who are exposed to gluten, the major storage protein of wheat and similar grains. An environmental factor, such as an infectious agent, is thought to precipitate the disease via various pathogenic mechanisms, such as molecular mimicry, resulting in modulation of the hosts immune tolerance. There is evidence that CD is related to perinatal infections, and that maternal-milk may have a protective role. Observations imply that there is a relationship between viral infections such as Adenovirus 12 and Hepatitis C virus and the development of CD. Understanding the relationship between infectious agents and autoimmunity may assist in prediction, early diagnosis and perhaps also the prevention of CD.

Pathogenesis of infertility and recurrent pregnancy loss in thyroid autoimmunity.

Thyroid autoimmunity is the most prevalent autoimmune state that affects up to 4% of women during the age of fertility. A growing body of clinical studies links thyroid autoimmunity as a cause of infertility and adverse pregnancy outcomes that includes miscarriage or preterm deliveries. Importantly, these adverse effects are persistent in euthyroid women. In the current review we elaborate on the pathogenesis that underlies infertility and increased pregnancy loss among women with autoimmune thyroid disease. Such mechanisms include thyroid autoantibodies that exert their effect in a TSH-dependent but also in a TSH-independent manner. The later includes quantitative and qualitative changes in the profile of endometrial T cells with reduced secretion of IL-4 and IL-10 along with hypersecretion of interferon-γ. Polyclonal B cells activation is 2-3 time more frequent in thyroid autoimmunity and is associated with increased titers of non-organ specific autoantibodies. Hyperactivity and Increased migration of cytotoxic natural killer cells that alter the immune and hormonal response of the uterus is up to 40% more common in women with thyroid autoimmunity. Lack of vitamin D was suggested as a predisposing factor to autoimmune diseases, and was shown to be reduced in patients with thyroid autoimmunity. In turn, its deficiency is also linked to infertility and pregnancy loss, suggesting a potential interplay with thyroid autoimmunity in the context of infertility. In addition, thyroid autoantibodies were also suggested to alter fertility by targeting zona pellucida, human chorionic gonadotropin receptors and other placental antigens.