[Residents' restricted hours of duty--who will benefit from it: patients, society or the physicians?].
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Humans↗
Biomedical subjects
Y Shoenfeld
Publications and source records attributed to Y Shoenfeld.
[Peer review--is there a better system?].
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Humans↗
[Hypophosphatemia as a prognostic measure of evaluation].
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Diabetic Ketoacidosis↗
Serum antibodies in epilepsy and seizure-associated disorders.
OBJECTIVE: To investigate whether autoantibodies to ion channels and other neural antigens are present in the sera of patients with epilepsy and seizure-related diseases. METHODS: Sera were obtained from 139 patients, including 26 with preexisting autoimmune disease, 46 in whom an autoimmune basis was suspected, and 67 with drug-resistant epilepsy. The sera were assayed for antibodies to voltage-gated potassium (VGKC) and calcium (VGCC) channels, glutamic acid decarboxylase (GAD), gangliosides, glutamate receptor type 3, cardiolipins, DNA, and nuclear antigens; the results were compared with results from a large cohort of healthy and disease controls. RESULTS: Increased titers of VGKC antibodies (>100 pM) were detected in 16 of 139 (11%) patients with seizures but only 1 control (0.5%). Eight VGKC-positive patients presented with an acute/subacute illness, and 5 of these had the highest VGKC antibodies; 3 patients improved spontaneously, another 5 patients responded well to immunomodulatory therapy. The other VGKC-positive patients had longer disease duration (>6 years) and intermediate levels of antibodies; immunotherapies have not been tested in this group. Very high levels of GAD antibodies (>1,000 U) were found in an additional 3 patients (2.1%) with long-standing drug-resistant epilepsy. CONCLUSIONS: The presence of autoantibodies to voltage-gated potassium channels and glutamic acid decarboxylase suggests that the immune system may contribute to certain forms of epilepsy or seizure-associated disorders. Further studies are needed to determine whether the antibodies are pathogenic.
Adolescent↗
Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the "Euro-Lupus Project".
The "Euro-Lupus Cohort" is composed by 1000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium--the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.
Age of Onset↗
Anti-serum amyloid component P antibodies in patients with systemic lupus erythematosus correlate with disease activity.
OBJECTIVE: To determine the presence of raised titres of anti-serum amyloid P component (SAP) antibodies in patients with systemic lupus erythematosus (SLE) and to evaluate their correlation with clinical disease by the SLEDAI and clinical manifestations. METHODS: 452 samples were screened for raised anti-SAP antibody titres by an ELISA. Clinical measures and SLEDAI scores were independently reviewed from medical records. 21 serial samples from 7 patients with SLE were assessed for a change in anti-SAP antibody titres after treatment. RESULTS: Raised anti-SAP antibody titres were detected in 145/328 (44%) SLE samples. In 112 randomly selected samples, 69/112 (62%) patients had raised anti-SAP antibodies and anti-dsDNA antibody titres, whereas only 32/112 (28%) had raised anti-dsDNA antibody titres without raised anti-SAP antibody titres. The mean titre of anti-SAP antibodies in patients with active disease was higher than in patients with inactive disease and controls. SLEDAI scores, assessed in 54 patients, were raised in 26/31 (84%) patients with raised anti-SAP antibody titres. A SLEDAI score >or=8 was found in 16/31 (52%) patients with raised anti-SAP antibody titres but in only 5/23 (22%) patients without raised titres. No specific pattern of disease was detected in patients with or without raised titres of anti-SAP antibodies. Serial sampling from patients with active SLE and raised anti-SAP antibody titres showed that anti-SAP antibody titres decreased after treatment and correlated with clinical improvement. CONCLUSION: Raised anti-SAP antibody titres detected in patients with SLE correlate with disease activity and decrease with improvement of clinical disease, and thus may serve as an additional prognostic marker.
Adolescent↗
Experimental models of systemic lupus erythematosus: anti-dsDNA in murine lupus.
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Animals↗
Close association between valvar heart disease and central nervous system manifestations in the antiphospholipid syndrome.
BACKGROUND: Heart valves lesions and central nervous system involvement are among the most common manifestations of the antiphospholipid syndrome (APS). OBJECTIVE: To evaluate possible interrelations between these manifestations in a large group of APS patients. METHODS: 284 APS patients were evaluated retrospectively, 159 of whom had primary APS. Cardiac-CNS associations were determined for the entire study population, and for subgroups of patients with primary APS or APS associated with systemic lupus erythematosus (SLE). RESULTS: Significant associations where found between cardiac vegetations and epilepsy (p < 0.02), and between cardiac valve thickening or dysfunction and migraine (p = 0.002). Borderline association was found between valvar vegetations and migraine (p = 0.09). A significant association was also found between all valvar lesions and stroke or transient ischaemic attacks. Subanalyses showed that patients with primary APS had significant associations between cardiac valve pathology and all CNS manifestations, while patients with APS associated with SLE had no such associations. CONCLUSIONS: The study suggests potential differences in biological behaviour between primary APS and APS associated with SLE. The presence of cardiac valve pathology may be a risk factor for several types of CNS involvement in PAPS.
Adolescent↗
Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome.
OBJECTIVE: To describe the characteristics of patients with catastrophic antiphospholipid syndrome (APS) included in the International Registry of patients with this condition (CAPS registry) and to analyse the value of the recently proposed preliminary criteria for the classification of catastrophic APS. METHODS: A review of the first 220 patients included in the website based CAPS registry was undertaken and the preliminary criteria for their classification were tested; 175 unselected patients with systemic lupus erythematosus or APS, or both, acted as controls. RESULTS: The mean age of the patients was 38 (14) years (range 7 to 74), with a female preponderance (F/M, 153/67). The main clinical manifestations included renal involvement in 154 (70%), pulmonary in 146 (66%), cerebral in 133 (60%), cardiac in 115 (52%), and cutaneous in 104 (47%); 114 patients (52%) recovered after the catastrophic APS event (mortality 48%). Patients who received the combination of anticoagulation plus steroids plus plasma exchange or intravenous immunoglobulins had the best survival rate (63%, p = 0.09). Sufficient data could be analysed for application of the classification criteria in 176 patients. According to the preliminary criteria, 89 patients (51%) could be classified as having "definite" and 70 (40%) as having "probable" catastrophic APS, thus given a sensitivity of 90.3% with a specificity of 99.4%. Positive and negative predictive values were 99.4% and 91.1%, respectively. CONCLUSIONS: The preliminary criteria for the classification of catastrophic APS and the CAPS registry are useful tools for epidemiological studies.
Adolescent↗
High-dose intravenous immunoglobulins: an option in the treatment of systemic lupus erythematosus.
Despite encouraging reports on the efficacy of intravenous immunoglobulin (IVIG) therapy in systemic lupus erythematosus (SLE), the clinical value of this treatment is not well established, and most of the data are based on case reports and small series of patients. IVIG has been used successfully to treat SLE patients with a broad spectrum of clinical manifestations, such as refractory thrombocytopenia, pancytopenia, central nervous system (CNS) involvement, secondary antiphospholipid syndrome, and lupus nephritis. The beneficial effects of IVIG on overall disease activity are usually prompt, with marked improvement within a few days, but they are often of limited duration. Improvement lasts for several weeks after the last infusion, although clinical response could be maintained by continuous monthly IVIG infusions. IVIG therapy immunomodulates autoimmune diseases by interacting with various Fcgamma receptors in such a way that it downregulates activating FcRIIA and FcRIIC and/or upregulates inhibitory FcRIIB. However, in SLE, additional mechanisms include inhibition of complement-mediated damage, modulation of production of cytokines and cytokine antagonists, modulation of T- and B-lymphocyte function, induction of apoptosis in lymphocytes and monocytes, downregulation of autoantibody production, manipulation of the idiotypic network, and neutralization of pathogenic autoantibodies. At present, IVIG in SLE is indicated either in severe cases that are nonresponsive to other therapeutic modalities, or when SLE can be controlled only with high-dose steroids; in such patients, IVIG thus becomes a useful steroid-sparing agent. However, this needs to be confirmed in double-blind, placebo-controlled studies.
Adjuvants, Immunologic↗
Multiplexed AtheNA multi-lyte immunoassay for ANA screening in autoimmune diseases.
BACKGROUND: Multiplexed assays using fluorescence microspheres is an exciting technology with multiple applications including the detection of antinuclear autoantibodies (ANA) and autoantibody profiles. It is a rapid, sensitive and automatic method for simultaneous quantitative detection of several autoantibodies. The aim of our study was to determinate ANA and other autoantibodies to the nine extractable nuclear antigens by the AtheNA Multi-Lyte ANA system and compare the results achieved by this method to the routinely used enzyme immunoassay. METHODS: Four hundred eighteen serum samples were tested utililizing the multiplexed method: 96 healthy donors, 86 requested ANA specimens obtained from routine lab, and 236 samples from patients with known autoimmune diseases (43-scleroderma, 113-systemic lupus erythematosus, 38-Sjogren's syndrome, and 42 rheumatoid arthritis). The ANA and antibodies to nine different analytes (SS/A, SS/B, Sm, RNP, Jo-1, Scl-70, dsDNA, Centromere B and Histone) were tested. RESULTS: ANA screening by AtheNA system revealed high concordance of 99 and 97.7% with the enzyme immunoassay test in samples obtained from healthy donors and ANA requested samples, respectively. Evaluation of autoimmune disease-related samples for ANA by AtheNA technology also confirmed a high rate of concordance of 92-97.7% and correlated with the enzyme immunoassay. Positive discrepant results were found for Scl-70 specificity in 12.7% of SLE specimens by AtheNA technology, while all tested sera were negative for this antibody by enzyme immunoassay. Negative discrepant results were observed by the AtheNA system for anti-dsDNA. The sera (15 randomly obtained samples from SLE patients) were positive for anti-dsDNA in 50% of samples in Farr assay and 55% in enzyme immunoassay, respectively. CONCLUSION: We suggest that the AtheNA technology may be a useful diagnostic tool for ANA screening. Additional investigations are required to compare an analytic performance between AtheNA and routine methods in determination of the individual autoantibody profile.
Antibodies, Antinuclear↗
Antibodies to glutamate receptor subtype 3 (GluR3) are found in some patients suffering from epilepsy as the main disease, but not in patients whose epilepsy accompanies antiphospholipid syndrome or Sneddon's syndrome.
Autoantibodies (Ab's) to the "B" peptide (amino acids 372-395) of glutamate/AMPA receptor subtype 3 (GluR3) are found in serum and cerebrospinal fluid of some patients with different types of epilepsy. Since such anti-GluR3B Ab's can activate and/or kill neurons in vitro and in vivo, they may contribute to epilepsy. To investigate whether anti-GluR3B Ab's may also be relevant to epilepsy when it accompanies some autoimmune-diseases, we tested for these Ab's in patients suffering from epilepsy that accompanies anti-phospholipid syndrome (APS) or Sneddon's syndrome (SNS), both being autoimmune-diseases with frequent neurological complications. We tested 77 pediatric patients whose epilepsy is their main disease; 31 adult patients whose epilepsy accompanies APS (primary or SLE-associated) or SNS; 45 epilepsy-free APS and SNS patients; and 90 healthy controls. Compared to the controls, significantly elevated anti-GluR3B Ab's were found in 22/77 (29%) patients whose epilepsy is their main disease, but in none of the patients whose seizures accompany APS or SNS. Yet, all the APS and SNS patients harbored the characteristic anti-phospholipid Ab's (aPL), directed against cardiolipin and beta2-glycoprotein I, and had lupus anti-coagulant. Thus, anti-GluR3B Ab's are not crossreactive with aPL, and not produced as a non-specific consequence of seizures on the one hand, or autoimmune-diseases on the other. Taken together with new findings accumulated recently in our lab, we suggest that anti-GluR3B Ab's are produced primarily in the periphery due to specific/non-specific "irritation" of the immune system, and that once they reach the brain via a leaky blood-brain barrier they may cause neuronal/glial damage and facilitate the outburst of epilepsy and additional neurological abnormalities. In contrast, the presence of anti-GluR3B Ab's does not seem to increase the probability of developing APS, SNS or the seizures that often accompany these autoimmune-diseases. These findings may have important diagnostic and therapeutic implications.
Adolescent↗
Antiphospholipid antibodies bind ATP: a putative mechanism for the pathogenesis of neuronal dysfunction.
Antiphospholipid antibodies (aPL) generated in experimental animals cross-react with ATP. We therefore examined the possibility that aPL IgG from human subjects bind to ATP by affinity column and an enzyme linked immunosorbent assay (ELISA). Sera with high levels of aPL IgG were collected from 12 patients with the antiphospholipid syndrome (APS). IgG fractions from 10 of 12 APS patients contained aPL that could be affinity-bound to an ATP column and completely eluted with NaCl 0.5 M. A significant (> 50%) inhibition of aPL IgG binding by ATP 5 mM was found in the majority. Similar inhibition was obtained with ADP but not with AMP or cAMP. All the affinity purified anti-ATP antibodies also bound beta2-glycoprotein-I (beta2-GPI, also known as apolipoprotein H) suggesting that, similar to most pathogenic aPL, their binding depends on this serum cofactor. We further investigated this possibility and found that the binding of beta2-GPI to the ATP column was similar to that of aPL IgG in that most was reversed by NaCl 0.5 M. Furthermore, addition of beta2-GPI to aPL IgG significantly increased the amount of aPL binding to an ATP column. We conclude that aPL IgG bind ATP, probably through beta32-GPI. This binding could interfere with the normal extracellular function of ATP and similar neurotransmitters.
Adenosine Triphosphate↗
The diagnostic utility of anti-cyclic citrullinated peptide antibodies, matrix metalloproteinase-3, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein in patients with erosive and non-erosive rheumatoid arthritis.
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.
Aged↗
Protective effect of intravenous immunoglobulin (IVIG) in an experimental model of pemphigus vulgaris.
Uncontrolled studies have found intravenous immunoglobulin (IVIG) to be effective in the treatment of pemphigus vulgaris (PV). The aim of this study was to evaluate the role of IVIG in preventing IgG autoantibodies binding to desmoglein-3 and blister formation using a controlled experimental design. The ability of IVIG to affect the binding of IgG affinity purified from two patients with PV to desmoglein-3 in comparison to IgG from one donor, was conducted by enzyme-linked immunosorbent assay (ELISA). The specificity was confirmed by competition assay. We assessed the effect of IVIG on the induction of experimental-PV in CD1 newborn mice by subcutaneous subjection of IgG affinity purified from two patients with PV. The treatment was conducted by subcutaneous administration of IVIG together with IgG from the pemphigus patients or appropriate control. The skin of the newborns was examined 24-48 h later for blisters, and samples of the affected areas were analysed by immunohistochemistry. IVIG as a whole molecule and its F(ab)(2) portion inhibited the binding of anti-desmoglein-3 antibody to recombinant desmoglein-3 in a dose-dependent manner. The specificity was confirmed by competition assays. In-vivo, IVIG and its F(ab)(2) portion prevented blister formation in the newborn mice. Cutaneous lesions were noted only in the groups of newborn mice who were injected with IgG fractions from the PV patients. Immunopathological evaluation revealed that IVIG prevented the formation of acanthylosis with IgG deposition in the intercellular spaces. These results point to the efficacy of IVIG in the prevention of blister formation in an experimental PV model.
Animals↗
Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease.
BACKGROUND AND AIMS: Several antibodies have been reported in the sera of patients with Crohn's disease (CD) and ulcerative colitis (UC). The most commonly described are anti-Saccharomyces cerevisiae mannan antibodies (ASCA) in CD and perinuclear antineutrophil cytoplasm antibodies (pANCA) in UC. Familial clustering of these antibodies has been described, suggesting they might be genetic markers. Our aim was to investigate the presence of these antibodies before the emergence of overt clinical manifestations. METHODS: Since 1980, the Israeli Defense Force (IDF) Medical Corps Serum Repository has stored serum samples obtained systematically from 5% of all recruits on enlistment, and from the same population on discharge from compulsory military service. We evaluated serum samples obtained from 32 subjects with CD and eight with UC before they were clinically diagnosed, along with samples from matched controls. RESULTS: ASCA were present in 10/32 (31.3%) CD patients before clinical diagnosis compared with 0/95 (0%) controls (p<0.001). None of the eight patients with serum samples available before diagnosis of UC were ASCA positive. ASCA was positive in 54.5% of patients after diagnosis of CD. The mean interval between ASCA detection and diagnosis was 38 months. In 90% of patients, antibodies were detected in the first available serum sample; therefore, measurements of the average time from the presence of ASCA to diagnosis may be even longer. pANCA were present in 2/8 (25%) patients with available sera before the diagnosis of UC. None of their 24 matched controls were positive (p = 0.014). CONCLUSIONS: ASCA and pANCA may predict development of inflammatory bowel disease years before the disease is clinically diagnosed.
Adult↗
Review: intravenous immunoglobulin therapy and thromboembolic complications.
Intravenous immunglobulin (IVIg) is used to treat a number of immune-deficiences and autoimmune diseases. Safety concerns related to a number of reported thromboembolic complications prompted us to review the literature. These complications happened mainly in individuals that had risk factors for thromboembolism, like advanced age, previous thromboembolic diseases, bed-ridden, and in individuals in which high doses or high infusion rates of IVIg were administered. The mechanism responsible for these events seems to be a rise in plasma viscosity that can trigger a thromboembolic event, especially in cases in which there is an underlying circulation impairment. Complications can be minimized by using IVIg only in clear-cut indications, weighting risk versus benefit in patients who are at high risk for thromboembolism and by sticking to carefully monitored slow infusion rates. IVIg for the treatment of autoimmune disorders should be administered as a five-day course of 2 g/kg of body weight. Each daily dose of 400 mg/kg should be given in not less than eight hours.
Autoimmune Diseases↗
Mycophenolate mofetil in animal models of autoimmune disease.
Mycofenolate mofetil (MMF-Cellcept) is an immunomodulatory drug utilized extensively in transplant medicine. The efficacy of regimes including Cellcept in preventing allograft rejection, and in the treatment of rejection, is now firmly established. The immunosuppressive actions of this drug enabled the investigation for the beneficial effects in autoimmune diseases. We review the evidence for the contribution of MMF in autoimmunity in animal models of systemic lupus erythematosus (SLE), mercury induced autoimmune glomerulonephritis, diabetes mellitus, experimental autoimmune uveoretinitis, and experimental allergic encephalitis. MMF has an influence on the T and B cell pathways. It is immunosuppressive and anti-inflammatory.
Animals↗