Hedi Orbach

Intravenous immunoglobulin: adverse effects and safe administration.

Intravenous immunoglobulin (IVIg) is administered for various indications and generally considered a safe therapy. Most of the adverse effects (AEs) associated with IVIg administration are mild and transient. The immediate AEs include headache, flushing, malaise, chest tightness, fever, chills, myalgia, fatigue, dyspnea, back pain, nausea, vomiting, diarrhea, blood pressure changes, tachycardia, and anaphylactic reactions, especially in IgA-deficient patients. Late AEs are rare and include acute renal failure, thromboembolic events, aseptic meningitis, neutropenia, and autoimmune hemolytic anemia, skin reactions, and rare events of arthritis. Pseudohyponatremia following IVIg is important to be recognized. Renal failure, usually oliguric and transient, occurs mostly on using sucrose-containing products owing to osmotic injury. Among high-risk patients who have a previous renal disease, dehydration, diabetes mellitus, advanced age, hypertension, hyperviscosity, or are treated by other nephrotoxic medications, administration of a non-sucrose-containing IVIg product after accomplishing hydration, in a low concentration and a slow infusion rate while supervising urine output and kidney function, is recommended. Thromboembolic complications occur because of hyperviscosity especially in patients having risk factors including advanced age, previous thromboembolic diseases, being bedridden, diabetes mellitus, hypertension, dyslipidemia, or those receiving high-dose IVIg in a rapid infusion rate. Immediate AEs can be treated by the slowing or temporary discontinuation of the infusion and symptomatic therapy with analgesics, non-steroidal anti-inflammatory drugs, antihistamines, and glucocorticoids in more severe reactions. Slow infusion rate of low concentration of IVIg products and hydration, especially in high-risk patients, may prevent renal failure, thromboembolic events, and aseptic meningitis.

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.

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.

Prolactin and autoimmunity

Sex hormones, especially estrogen and prolactin (PRL), have an important role in modulating the immune response. PRL is secreted from the pituitary gland as well as other organs and cells particularly lymphocytes. PRL has an immune stimulatory effect and promotes autoimmunity. PRL interferes specifically with B cell tolerance induction, enhances proliferative response to antigens and mitogens and increases the production of immune globulins, cytokines and autoantibodies. Hyperprolactinemia (HPRL) in women present with clinical manifestations of galactorrhea, primary or secondary amenorrhea, delayed menarche or a change in the menses either in the amount or in the regularity. Furthermore in the last 2 decades multi-organ and organ specific autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogrens syndrome (SS), Hashimotos thyroiditis (HT), multiple sclerosis (MS), psoriasis, hepatitis C patients, Behçets disease, peripartum cardiomyopathy (PPCM) and active celiac disease were discussed to be associated with HPRL. There is data showing correlation between PRL level and diseases activity in few diseases. Genetic factors may have a role in humans as in animal models. The PRL isoforms based on the differences in the amino acid sequence and size of the cytoplasmic domain have an important effect on the bioactivity on prolactin receptors (PRL-Rs).

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.

Prolactin and autoimmunity: hyperprolactinemia correlates with serositis and anemia in SLE patients.

Evidence points to an association of prolactin to autoimmune diseases. We examined the correlation between hyperprolactinemia and disease manifestations and activity in a large patient cohort. Age- and sex-adjusted prolactin concentration was assessed in 256 serum samples from lupus patients utilizing the LIASON prolactin automated immunoassay method (DiaSorin S.p.A, Saluggia, Italy). Disease activity was defined as present if European Consensus Lupus Activity Measurement (ECLAM) > 2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) > 4. Lupus manifestations were grouped by organ involvement, laboratory data, and prescribed medications. Hyperprolactinemia was presented in 46/256 (18%) of the cohort. Hyperprolactinemic patients had significantly more serositis (40% vs. 32.4%, p = 0.03) specifically, pleuritis (33% vs. 17%, p = 0.02), pericarditis (30% vs. 12%, p = 0.002), and peritonitis (15% vs. 0.8%, p = 0.003). Hyperprolactinemic subjects exhibited significantly more anemia (42% vs. 26%, p = 0.02) and marginally more proteinuria (65.5% vs. 46%, p = 0.06). Elevated levels of prolactin were not significantly associated with other clinical manifestations, serology, or therapy. Disease activity scores were not associated with hyperprolactinemia. Hyperprolactinemia in lupus patients is associated with all types of serositis and anemia but not with other clinical, serological therapeutic measures or with disease activity. These results suggest that dopamine agonists may be an optional therapy for lupus patients with hyperprolactinemia.

Autoantibody Screen in Inflammatory Myopathies High Prevalence of Antibodies to Gliadin

Background: Inflammatory myopathies (IM) are associated with autoimmune diseases. Aim: To evaluate the titers of auto‐antibodies specific to various autoimmune diseases in patients with IM compared with controls. Methods: Sera from 99 IM patients and 100 healthy controls were tested for autoantibodies for vasculitis (myeloperoxidase, PR3, and glomerular basement membrane) and autoimmune gastrointestinal diseases (IgA and IgG antigliadin, antitissue transglutaminase, and Saccharomyces cerevisiae) utilizing the BioPlex 2200 Multiplexed Immunoassay method (Biorad). Results: Antigliadin IgA levels were significantly elevated in IM patients compared with controls (0.37 units ± 0.44 vs. 0.24 units ± 0.15, P= 0.017). Antitissue transglutaminase IgA was marginally increased in IM patients versus controls (0.36 units ± 1.12 vs. 0.2 units ± 0.0, P= 0.08). Conclusions: Antibodies to gliadin and tissue transglutaminase characteristic for celiac disease were elevated in patients with IM compared with controls. This may indicate a higher prevalence of gluten sensitivity or celiac disease in IM.

Sex and Gender Differences in Autoimmune Diseases

Autoimmune and rheumatological diseases often come to mind when thinking about gender differences in medicine.

Social values as an independent factor affecting end of life medical decision making

Research shows that the physician’s personal attributes and social characteristics have a strong association with their end-of-life (EOL) decision making. Despite efforts to increase patient, family and surrogate input into EOL decision making, research shows the physician’s input to be dominant. Our research finds that physician’s social values, independent of religiosity, have a significant association with physician’s tendency to withhold or withdraw life sustaining, EOL treatments. It is suggested that physicians employ personal social values in their EOL medical coping, because they have to cope with existential dilemmas posed by the mystery of death, and left unresolved by medical decision making mechanisms such as advanced directives and hospital ethics committees.

Novel approaches to therapy for systemic lupus erythematosus: update 2005

This review covers the major advances in the therapeutic potentials related to systemic lupus erythematosus published in Medline between 2000 and February 2005. Controlled, open and Phase I–III trials were included. Anecdotal reports were excluded. Several trials have defined the role of cyclophosphamide, methotrexate, antimalarials, hormonal treatment and mycophenolate mofetil (Cellcept) in the management of systemic lupus erythematosus. The aims of novel biologics for systemic lupus erythematosus are to target the autoimmune disease at different points: B-cell depletion (rituximab [Rituxan®], anti-BLys antibodies [Lymphostat-B™]), inhibition of T–B interaction (rituximab), blockade of cytokines (anti-interleukin-10 antibodies), manipulation of idiotypes (intravenous immunoglobulin), tolerance induction to DNA and immunoglobulin-peptides and peptide therapy (abetimus sodium [Riquent®]). Low-dose intravenous cyclophosphamide (Euro-Lupus protocol) is as effective as the conventional National Insitutes of Health protocol and is also associated with less toxicity. Stem cell transplantation for severe disease induces remission in most patients, however, the relapse rate in a third of patients and the associated morbity and mortality restricts its use to selected patients with life-threatening disease. Intravenous immunoglobulin, although utilized in open trials, is effective and safe for various manifestations of systemic lupus erythematosus. Major advances have been associated with mycophenolate mofetil and rituximab. Mycophenolate mofetil is effective for induction and maintenance therapy of lupus proliferative glomerulonephritis and is associated with fewer adverse events than monthly intravenous cyclophosphamide. Rituximab is a promising agent, and although its utilization is presently limited, it appears to be effective for lupus patients with severe disease.