A liposomal steroid nano-drug for treating systemic lupus erythematosus.

BACKGROUND: Glucocorticoids have been known for years to be the most effective therapy in systemic lupus erythematosus. Their use, however, is limited by the need for high doses due to their unfavorable pharmacokinetics and biodistribution. We have previously developed a novel liposome-based steroidal (methylprednisolone hemisuccinate (MPS)) nano-drug and demonstrated its specific accumulation in inflamed tissues, as well as its superior therapeutic efficacy over that of free glucocorticoids (non-liposomal) in the autoimmune diseases, including the adjuvant arthritis rat model and the experimental autoimmune encephalomyelitis mouse model. OBJECTIVES: In the present work we have evaluated the therapeutic effect of the above liposome-based steroidal (MPS) nano-drug in the MRL-lpr/lpr murine model of SLE and compared it with similar doses of the free MPS. METHODS: MRL-lpr/lpr mice were treated with daily injections of free MPS or weekly injections of 10% dextrose, empty nano-liposomes or the steroidal nano-drug and the course of their disease was followed up to the age of 24 weeks. RESULTS: Treatment with the steroidal nano-drug was found to be significantly superior to the free MPS in suppressing anti-dsDNA antibody levels, proliferation of lymphoid tissue and renal damage, and in prolonging survival of animals. CONCLUSION: This significant superiority of our liposome based steroidal nano-drug administered weekly compared with daily injections of free methylprednisolone hemisuccinate in suppressing murine lupus indicates this glucocorticoid nano-drug formulation may be a good candidate for the treatment of human SLE.

Rituximab induces resolution of recurrent diffuse alveolar hemorrhage in a patient with primary antiphospholipid antibody syndrome.

Diffuse alveolar hemorrhage (DAH) is a rare manifestation of primary antiphospholipid antibody syndrome (APS). We describe a patient with primary APS and refractory recurrent episodes of DAH. The patient was admitted 15 times due to recurrent episodes of DAH in a period of 18 months. Multiple immunosuppressive drugs did not improve his condition. Two years after his presentation, he was treated with rituximab (two doses of 1 g, 2 weeks apart). Six months later, the attacks of DAH have gradually disappeared. In a follow-up of more than 2 years after he received rituximab, the patient has had no further admissions due to DAH. Levels of antiphospholipid antibodies were measured during follow-up of 4 years. Anti-ß2 glycoprotein IgG titer decreased to normal 6 months after therapy but anticardiolipin (aCL) antibody titer increased. We conclude that rituximab caused a dramatic clinical response in this patient. Anti-ß2 glycoprotein IgG correlated better with the clinical response in this patient than aCL.

Antibodies against the VRT101 laminin epitope correlate with human SLE disease activity and can be removed by extracorporeal immunoadsorption.

OBJECTIVE: We have previously shown that murine pathogenic lupus autoantibodies bind to VRT101, a 21-mer peptide located at the globular part of the laminin-alpha chain. In this study, we evaluated whether VRT101 also serves as a target for human lupus antibodies, upholding the hypothesis that VRT101 may serve as a potential target in the therapy of lupus. METHODS: Anti-VRT101 and anti-dsDNA reactivity were measured in the serum of lupus patients and compared with that of healthy individuals and patients with other rheumatic disorders. Statistical correlations between disease activity measured by the SLEDAI-2k scale and compatible serum anti-VRT101 and anti-dsDNA levels were defined. A VRT101-coupled sepharose column was assessed for its efficacy in removing serum anti-VRT101 antibody and its safety in extracorporeal apheresis in sheep. RESULTS: Anti-VRT101 and anti-dsDNA antibodies were significantly higher in SLE patients compared with patients with other rheumatic conditions. A high degree of correlation was detected between anti-VRT101 levels and the SLEDAI-2k activity in patients with SLE. Immunoadsorption of lupus patients' sera on the VRT101-sepharose column removed most of the anti-VRT101 antibodies. The column was found to transfer effectively 3l of normal sheep plasma without significant removal of non-specific antibodies or other proteins. CONCLUSIONS: Anti-VRT101 anibodies are abundantly detected in the serum of patients with SLE and correlate with disease activity. Specific removal of serum anti-VRT101 by extracorporeal plasmapheresis with specific immunoadsorption on the VRT101-coupled sepharose columns may serve as a new therapeutic tool for specific immunoadsorption of pathogenic antibodies in SLE patients.

Outcome of a national Israeli cohort of pediatric systemic lupus erythematosus.

The aim of this study was to describe the clinical manifestations and outcomes of a national cohort of childhood systemic lupus erythematosus (cSLE). All cases of cSLE registered in the Israeli national registry of children with rheumatic diseases between 1987-2003 were examined for disease activity and damage by the SLE disease activity index (SLEDAI) and SLE collaborating clinics/American College of Rheumatology (SLICC/ACR) damage index. Demographic, clinical, laboratory and treatment factors were analysed for their effect on the outcome. One-hundred and two patients were identified, 81% females, with a mean age at diagnosis of 13.3 +/- 2.6 years. The mean SLEDAI score was 17.2 +/- 9.0 (range 2-60). Fifty four patients were followed for at least five years. The mean SLEDAI decreased to 7.6 +/- 6.3 (0-29) and the mean SLICC/ACR damage index was 0.7 +/- 1.6 (0-8). Five patients developed chronic renal failure. No patients died. No factors were found to be significantly associated with the outcome except the initial SLEDAI score. The five-year outcome of our national cSLE cohort was good; with relatively low activity and minimal damage in most patients. The initial SLEDAI predicted the development of late damage.

Alveolar hemorrhage in cryoglobulinemia--an indicator of poor prognosis.

OBJECTIVE: Alveolar vasculitis is an unusual event in the course of cryoglobulinemia (CG). The inflammatory process involving the alveolar capillary walls may result in severe alveolar hemorrhage and consequently lead to a grave outcome. The objective of this study was to evaluate the occurrence of this unusual finding in CG. METHODS: We reviewed the records of all patients with CG who developed acute alveolitis, registered their associated clinical and laboratory parameters and evaluated the possible impact these parameters may have on their prognosis. In addition we scanned the Medline for similar cases. RESULTS: Of the 125 patients with CG who were hospitalized in our medical center during the last 23 years, 4 (3.2%) developed alveolar hemorrhage. All patients exhibited extreme fatigue, fever with clinical and radiological evidence of alveolitis. Of the 4 new cases, 1 had type II CG and 3 had type III CG. Of our 4 patients, 3 developed concomitant acute renal failure necessitating hemodialysis. A literature survey resulted in 6 additional cases. All 10 patients experienced acute respiratory insufficiency and eight had at least one episode of hemoptysis. In the other 2 patients the bronchoalveolar lavage (BAL) fluid contained hemosiderin laden macrophages. Five of the 10 patients had concomitant hepatitis C virus (HCV) infection; 2 patients were seen prior to modern identification of the HCV; however, liver abnormalities were not described. Of the 10 patients 5 patients had type II CG and 5 others had type III. Of the 7 patients in whom outcome was available, 6 died from their illness. Acute renal failure or exacerbation of antecedent glomerular disease occurred in 8 patients. CONCLUSIONS: Alveolitis is a rare manifestation of CG, presenting as an overwhelming systemic illness and portends a poor prognosis with a high mortality rate.

The future of the treatment of systemic lupus erythematosus.

Despite recent advances, patients with systemic lupus erythematosus (SLE) still experience considerable morbidity and mortality. To try and improve their prognosis, varied novel biological interventions and immune manipulations are being developed. They may hold promise in particular for patients whose disease is organ-threatening and refractory to conventional treatment. In addition, awareness of the tendency of lupus patients to develop accelerated atherosclerosis as well as newly gained insights into the underlying mechanisms, may lead to better control of risk factors, earlier diagnosis of prevalent cardiovascular disease and more effective treatment. Infections also remain a significant threat that may be amenable to improved preventive measures. Evidence related to a better management of lupus patients by specialists, the need to address the impact of commonly associated stress and depression and other significant developments are also presented and discussed.

Hyperacute renal failure as the initial presentation of systemic lupus erythematosus.

SLE nephritis is usually a slow process that may lead to renal failure many years after its first presentation. Success of different therapeutic modalities in preventing renal failure is therefore evaluated and compared only after many years of treatment. Lately, this conservative philosophy has been challenged with the acknowledgment of collapsing glomerulopathy (CG), a recent recognized clinical-pathological entity, characterized by rapidly progressive renal failure. Despite this ominous description we present an unusual case of a patient who presented with systemic lupus erythematosus (SLE) and clinical and pathological findings of CG, who completely remitted several weeks after commencing immunosuppressive therapy with intravenous cyclophosphamide and prednisolone.

Structural considerations of autoantibodies.

The mechanisms responsible for peptide-induced immunosuppression lupus-prone BWF1 mice were determined to be mediated via recognition by T cells, although the response was peptide-specific, as some accelerated the autoimmune response. Furthermore, this was associated with suppression of IFN-g and IL-4 in serum and increased TGF-b. Recent isolation of peptide-specific T cells should be helpful in sorting out the mechanisms responsible for these events. In separate studies, it was demonstrated that an anti-DNA antibody that enters cells is able to transport proteins linked to it, supporting the possibility that this system can be used as a therapeutic modality to modify specific cellular activities.

Constitutive hyperhistaminaemia: a possible mechanism for recurrent anaphylaxis.

The process underlying anaphylaxis involves an uncontrolled elevation in blood levels of mediators, including histamine. Usually, these abnormal levels are attributed to the degranulation of basophils and mast cells. Few reports have assessed the contribution of defects in histamine pharmacodynamics to allergic responses. In this report we describe a patient with recurrent anaphylaxis who was initially suspected to have enhanced histamine intolerance. We evaluated urine and blood samples collected from this patient and from control individuals using an ELISA test. Our data clearly show constitutive hyperhistaminaemia and a markedly impaired urinary histamine clearance ratio in the index patient. It is suggested that this defect facilitates anaphylaxis.

Anti-DNA antibodies cross-reacting with laminin inhibit trophoblast attachment and migration: implications for recurrent pregnancy loss in SLE patients.

PROBLEM: Systemic lupus erythematosus (SLE), an autoimmune disease, is associated with reduced fetal survival, recurrent abortions, and other pregnancy complications. Some of the autoantibodies found in SLE bind to laminins (LNs), which play an important role in the implantation of the fertilized ovum in humans. METHOD OF STUDY: To elucidate the role of these specific autoantibodies, chorionic villous explants from 6 7-week-old human placentas were established as organ cultures on laminin-1 (LN-1), collagen IV (CN-IV) or uncoated culture dishes. The cultures were then exposed to a mouse monoclonal anti-DNA/anti-LN-1 antibody, to human polyclonal lupus antibodies cross-reacting with LN-1, a function-blocking polyclonal antibody to LN-1, polyclonal antibodies to CN-IV, or IgG control. RESULTS: The explants attached to LN-1 and CN-IV, but not to uncoated culture dishes. LN-1 promoted migration of trophoblast, whereas CN-IV promoted migration of fibroblast-like cells. Trophoblast attachment and migration were abolished in a dose-dependent manner by all three antibodies to LN-1, but not by antibodies to CN-IV or IgG control. Furthermore, the effect of anti-LN antibodies was abolished by preincubating them with LN-1. CONCLUSIONS: These studies suggest that anti-DNA antibodies cross-reacting with LNs may play a role in early pregnancy failure in SLE patients by interfering with placental implantation.

Abundance of house dust mites in relation to climate in contrasting agricultural settlements in Israel.

The correlation between climatic conditions and mite numbers in houses from rural areas was studied in 13 agricultural communities (kibbutzim and moshavim) in nine geo-climatic subregions of Israel. Mites were present in 97% of the dust samples. The average number of mites per gram of dust in the different localities ranged between 84 and 2053. The maximum number of mites (7440/g dust) was found in a carpet from a house in Geva Carmel in the northern coastal region. The most prevalent species of mites were Dermatophagoides pteronyssinus and Dermatophagoides farinae, which were found in 85.6% and 71.3% of the samples, respectively. The house dust mites D. pteronyssinus, D. farinae and Euroglyphus maynei constituted 94.8% of the mites. Most of the mites were isolated from the carpets and sofas (37.0% and 33.7%, respectively), and a smaller number from beds (29.3%). The smallest number of mites (< or = 250/g dust) were found at a minimum relative humidity (RH) of 30% and lower, with a maximum temperature of 32 degrees C and higher, i.e. in the Jordan valley and Negev mountains. A greater number of mites (250-500/g dust) were found at a minimum ambient RH of 35-40% and a maximum temperature of 32 degrees C and higher, i.e. the Hula valley. A large number of mites (500-1000/g dust) were found at a minimum RH of 35-40% with a maximum temperature of 30 degrees C and lower, i.e. in the Judean and Samarian range, as well as in upper Galilee. The largest number of mites (1000-2000/g dust) was found at a minimum RH of 45% and higher, with a maximum temperature ranging between 30 and 32 degrees C. These conditions occur in the coastal strip, the coastal plain and in the Judean and Samarian foothills. A monthly examination of two houses in Zova, a kibbutz in the Judean hills next to Jerusalem, and two houses from Palmachim, a kibbutz in the coastal region, revealed that the highest prevalence of mites was found in the months April-November and May-November, respectively. In Zova, the highest number of mites were found during the months of June and July while the highest concentrations of D. pteronyssinus-antigen (Der p I) were measured during the month of September. A positive correlation between mite numbers and the quantity of Der p I in house dust was found.

Plasma immunoglobulins in patients with severe ovarian hyperstimulation syndrome.

OBJECTIVE: To assess immunoglobulin (Ig) concentrations in plasma and ascitic fluid of patients with severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Controlled clinical study. SETTING: Tertiary medical center. PATIENT(S): Ten patients with severe OHSS after ovulation induction for IVF and 10 controls who had undergone similar ovulation induction and did not develop OHSS. INTERVENTION(S): Three blood samples were obtained from each OHSS patient: one at the time of hospitalization for severe OHSS, one when significant clinical improvement was evident, and one at the first follow-up visit after discharge from the hospital. Blood samples were drawn from control patients 6-8 days after ET. Ascitic fluid was obtained from all patients with OHSS by therapeutic paracentesis. MAIN OUTCOME MEASURE(S): Immunoglobulin concentrations were assayed by radial immunodiffusion. RESULT(S): Significantly lower levels of gamma-globulins, specifically IgG and IgA, were detected in the plasma of patients with severe OHSS, whereas alpha- and beta-globulin levels as well as IgM levels were not significantly different from those in controls. Both IgG and IgA levels increased as patients clinically improved. Ascitic fluid contained high IgG, moderate IgA, and negligible IgM levels. CONCLUSION: Severe OHSS is characterized by hypogammaglobulinemia, attributed to leakage of medium-molecular-weight immunoglobulins such as IgG and IgA to the peritoneal cavity.

Koch's postulates and autoimmunity: an opposing viewpoint.

Autoimmunity is characterized as a state of abnormal specific humoral and cell-mediated responses against constituents of body tissues. One time-honored approach to explaining the pathogenesis of autoimmunity has been application of the Koch's postulates, on loan from the field of microbiology suggesting that autoantibodies and/or autoreactive T cells are the presumed "pathogens" of autoimmunity, and that passive transfer of these autoimmune factors to susceptible animals will result in the induction of the autoimmune disease. We suggest that autoimmunity is not in many cases due to the presence of factors leading to the autoimmune response in those susceptible. Instead, it is the lack of a factor which leads to the development of autoimmunity, a factor (cytokine, protein, gene, etc.) which is present in the healthy individual and normally protects in from disordered immune regulation. We propose to direct more research into therapeutic modulation of autoimmunity by administration of putative "protective factors", rather than by attempts to depress or remove autoreactive cells and antibodies from the autoimmune.

Gastric-Mucocutaneous gammadelta T cell lymphoma: possible association with Epstein-Barr virus?

Gammadelta T cell lymphoma is usually either subcutaneous or hepato-splenic and involvement of other extranodal sites is rare. Here we report an unusual case of gammadelta T cell lymphoma involving the subcutaneous tissue, vocal cords, gastric mucosa and the central nervous system with a rapidly progressive clinical course and fatal outcome. Epstein-Barr virus (EBV) was shown to be present in the tumor cells, and is thought to play a role in the pathophysiology of this particular case of lymphoma.

Hereditary CD4+ T lymphocytopenia.

Two siblings suffering from mental retardation, progressive bronchiectasis, extensive warts, and persistent hepatitis B are described. The propositus also had an unusual physiognomy and non-specific colitis. Both patients had a marked decrease in the population of CD4+ helper T cells.

Down-regulation of surface antigens recognized by systemic lupus erythematosus antibodies on embryonal cells following differentiation and exposure to corticosteroids.

We have previously suggested that anti-DNA antibodies present in systemic lupus erythematosus patients can bind directly to tissues as a result of cross-reactivity with embryonal tissue-based antigens. Here we have analyzed the interaction between polyclonal and monoclonal mouse and human lupus autoantibodies and an embryonal cell line. We report that a murine embryonal stem cell line (ES) expresses a surface antigen which is recognized by mouse and human lupus autoantibodies. This surface antigen is down-regulated following maturation of the cells or incubation with corticosteroids. Adhesion molecules may serve as the target membrane antigen in ES cells since preincubation with these antibodies decreases the ability of ES cells to adhere to the plate.