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Abstract Objective: To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies). Design: Randomised controlled trial. Setting: Specialist clinic for recurrent miscarriages. Subjects: 90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies. Intervention: Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks' gestation. Main outcome measures: Rate of live births with the two treatments. Results: There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%). Conclusion: Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone. Key messages The prognosis for pregnancies in women with recurrent miscarriage associated with phospholipid antibodies is poor This randomised controlled trial found that the prognosis improved with low dose aspirin and was further improved with the addition of low dose heparin to the aspirin This combination may promote successful embryonic implantation in the early stages of pregnancy and protect against thrombosis of the uteroplacental vasculature after successful placentation Most miscarriages occurred before 13 weeks' gestation Nearly a quarter of the successful pregnancies were delivered prematurely (before 37 weeks' gestation), so close surveillance is necessary Long term use of low dose heparin was associated with few complications

The role of antiphospholipid antibodies (aPL), which are not included in the Sydney diagnostic criteria, in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) is poorly understood. The aim of this study was to determine the clinical significance of IgG antibodies for domain 1 of β -glycoprotein 1 (β -GP1), IgG anti-β -GP1DI, in patients with APS with and without SLE. The study included 187 patients with APS with or without SLE, 49 patients formed the comparison group, and 100 apparently healthy individuals formed the control group. IgG/IgM antibodies to cardiolipin (aCL) and IgG/IgM anti-β -GP1 were determined by enzyme immunoassay (ELISA) in patients with or without APS, and IgG anti-β -GP1DI was determined by chemiluminescence assay (CLA) in all patients and controls. IgG anti-β -GP1DI was detected in 37 (71%) of 52 patients with primary APS (PAPS), in 6 (50%) of 12 patients with probable APS, in 42 (71%) of 59 patients with SLE + APS, in 17 (26%) of 64 patients with SLE, in 1 (2%) of the comparison group, and in none of the control group. IgG anti-β -GP1DI was significantly associated with PAPS and SLE + APS compared with the patients with SLE (p = 0.0002 and 0.0001, respectively). The association of IgG anti-β -GP1DI with clinical manifestations of APS (thrombosis (p = 0.001) and obstetric pathology (p = 0.04)) was detected. There was a significant association of IgG anti-β -GP1DI with arterial thrombosis (p = 0.002) and with late gestational obstetric pathology (p = 0.01). High specificity of IgG anti-β -GP1DI depending on the diagnosis and clinical manifestations of APS despite low sensitivity was noted: specificity was 84% for thrombosis, 94% for obstetric pathology, and 89% for APS. Isolated IgG anti-β -GP1DI positivity was reported in 2% of 50 aPL-negative patients and was not associated with APS manifestations. The frequency of IgG anti-β -GP1DI detection was higher in the patients with APS compared to the patients with SLE, comparison group, and control (p < 0.05). Positive IgG anti-β -GP1DI values were significantly associated with thrombotic complications and with obstetric pathology (p = 0.002 and p = 0.01, respectively). Specificity of IgG anti-β -GP1DI for APS and its clinical manifestations (thrombosis and obstetric pathology) was higher than sensitivity (89, 94, and 84%, respectively).

Background Of all anti-dsDNA antibody detection methods, the Crithidia luciliae immunofluorescence test (CLIF) is considered to have the highest specificity for systemic lupus erythematosus (SLE). Objective The objective of this report is to evaluate whether the presence of anti-dsDNA antibodies detected by the CLIF method is associated with a specific clinical phenotype in recently diagnosed SLE. Methods This retrospective cross-sectional study included all patients with newly diagnosed SLE between 1990 and 2011 and followed up in our institution. Demographic, clinical and laboratory findings were assessed. Correlations between positivity of anti-dsDNA by the CLIF method, clinical and laboratory data were analyzed. Results A total of 104 patients were included in the analysis. Patients who were positive for anti-dsDNA by the CLIF method at the time of diagnosis had (statistically) significantly higher titers of anti-dsDNA by the ELISA method, antinuclear (ANA) and anticardiolipin antibodies, lymphopenia and complement consumption compared with the other two groups. Also they presented significantly more musculoskeletal symptoms at baseline. Conclusion The presence of anti-dsDNA by the CLIF method in newly diagnosed SLE was associated with certain markers of increased disease activity. Its use could be a useful biomarker for a specific clinical phenotype suggestive of a more severe involvement at the time of the diagnosis.

ANA IIF is an effective screening assay in patients with clinical features of SLE and will detect most anti-ssDNA, anti-dsDNA, ENAs, and other autoantibodies. False positives are common. The clinical importance cannot be extrapolated from the ANA titre or pattern, although higher titres (> 1/160) are more likely to be important. HEp-2 cells are the most sensitive substrate for ANA detection, but this must be balanced against an increased incidence of insignificant positivity. ANA positive samples should be subjected to more specific assays for the diagnosis of SLE. A combination of ENA (Ro/La/Sm/RNP) and dsDNA assays will detect most patients with SLE as long as the characteristics of the assays used are well understood. ESR and CRP measurements provide useful additional information. Sjogren's syndrome and MCTD will produce overlapping serology with SLE, and anti-dsDNA titres are sometimes seen in autoimmune hepatitis and rheumatoid arthritis. All results should be reported in the light of the clinical details, by an experienced immunologist. A suggested diagnostic protocol is outlined in fig 1. The type of assay used crucially influences the predictive value of the tests. ELISA technology dominates routine laboratory practice, but tends to produce more false positive and true weak positive results, which may reduce the PPV of the test. This can be minimised by using IgG specific conjugates and careful assay validation. The NPV for SLE [figure: see text] is high for most assays but the PPV varies. Where necessary, laboratories should use crithidia or Farr dsDNA assays to confirm dubious ELISA dsDNA results, and ID/IB to confirm dubious ENA results. For monitoring, a precise, quantitative assay is required. It is unclear whether the detection of IgM or low affinity antibodies has a role here. A combination of anti-dsDNA, C3, C4, CRP, and ESR assays provides the most useful clinical information. Anti-ssDNA assays are likely to be useful, and are potentially more robust than anti-dsDNA assays, but require more validation. Local validation of individual assays and EQA participation is essential. Not all assays that apparently measure the same antibody specificities have equal clinical relevance, even within a single technology. Insufficient international or national reference preparations are currently available for many antibody specificities to enable effective standardisation. Quality assurance schemes reveal large differences in units reported by different assays for some analytes, even when calibrated against an IRP or equivalent reference preparation. Serial results can therefore only be compared from the same laboratory at present. Most autoantibodies increase during active disease, but few prospective data are currently available to justify treatment on the basis of rising titres. Further randomised prospective studies are required to examine the importance of antibody isotype and affinity in the monitoring of SLE by individual assay methods. The most important aspect of the appropriate use of laboratory assays is to become familiar with the limitations of the technology currently in use in your local laboratory, and to consult with your clinical immunologist in cases of doubt, preferably before commencing serological screening.

Nodular regenerative hyperplasia (NRH) of the liver is a rare disorder that is often associated with connective tissue disorders, haematological malignancy, or drugs, and is a cause of non-cirrhotic portal hypertension. We describe two cases of NRH in individuals with adult coeliac disease and IgA anticardiolipin antibodies. We discuss the potential impact of this observation on the understanding of the pathogenesis of NRH.

In an effort to improve the quantitative detection of anticardiolipin antibodies (aCL) IgG so as to classify patients correctly as antiphospholipid syndrome (APS) positive, we developed a new immunoassay based on a sandwich time-resolved fluoroimmunoassay (TRFIA) using the complex of cardiolipin plus bovine β 2 GPI as antigen and Eu 3+ -labeled rabbit antihuman IgG as conjugate. The precision, sensitivity, specificity, and stability of the assay were evaluated, and comparison with the classical ELISA was also made. The aCL IgG TRFIA kit we established had a wider detectable range than three commercial ELISA ones from different manufacturers when a specimen was diluted, with strong positive result from 1:12.5 to 1:204,800. The average intra-assay and inter-assay CVs detected by the aCL IgG TRFIA was 3.14 and 3.70 %, respectively. The sensitivity was 0.1 GPL U/ml, and the clinical diagnostic specificity was 98 %. The established assay kit also behaved better in stability than the commercial ELISA ones. Additionally, the immunoassay we established correlated well with the ELISA, and the correlation coefficient was 0.975. We thus conclude that the TRFIA we developed for aCL IgG detection gives promise to a more sensitive and reliable diagnosis of APS and has potential value for large-scale screening programs.

Different immune disorders are involved in the development of sudden sensorineural hearing loss (SSNHL). This includes a wide spectrum of immune-mediated disorders such as immune complexes, production of autoantibodies to the inner ear proteins, production of anticardiolipin (aCL) antibodies, and cellular immune defects. Some studies have also found an elevation of total IgE levels and a type 1 immune reaction. Our objective was to establish the association of “idiopathic” SSNHL (ISSNHL) with various autoantibodies, and to analyze the persistence over time of existing aCL and anti–β2 glycoprotein 1 (anti–β2 GP1) antibodies in such patients. Finally, we sought to establish a possible association between ISSNHL and total IgE elevation and whether this elevation is due to a specific type I immune reaction. In this prospective follow-up study, 51 patients considered as having ISSNHL were compared with 35 age-sex matched healthy volunteers over a 3-year period. All participants were tested for serum antinuclear antibodies, antithyroid antibodies, aCL, and rheumatoid factor. All patients who were positive for aCL antibodies were reanalyzed 3 months later for aCL antibody persistence and for the coexistence and persistence of anti-β2 GP1 antibodies. Skin prick tests were performed in patients in whom total IgE was elevated. Antinuclear antibodies were positive in 9 of 51 (17%) and antithyroid antibodies in 11 of 51 (21%) ISSNHL patients, as compared to 1 of 35 (3%) and 2 of 35 (6%), respectively, in the control group. Rheumatoid factor was positive in 6 of the 51 patients (12%) and in none of the control group. Positive aCL antibodies were present in 16 of 51 patients (31%), 6 of whom (12%) were also positive for anti–β2 GP1 antibodies. Three months later, aCL antibodies persisted in 7 patients (14%), and anti–β2 GP1 in 4 patients. Only 2 of the normal subjects (6%) were positive for aCL antibodies, which persisted in only 1 of them (3%). The level of total IgE was elevated in 14 of 51 patients (27%), in contrast to 3 of 35 controls (8%). Six of them (42%) demonstrated a positive skin test to at least 1 allergen, but only 3 presented allergy symptoms. Our findings support the reported existence of multiple immune-mediated disorders in patients with ISSNHL. The lack of aCL antibody persistence in as many as half of our patients strongly suggests that transient phenomena (eg, viral infection) may trigger aCL antibody activity. However, the presence of aCL antibodies, especially in conjunction with anti–β2 GP1 antibodies, suggests that in some patients, SSNHL is included among the rare symptoms of the antiphospholipid syndrome.

Objective: To assess the occurrence of anticardiolipin antibodies (ACA) (as well as of anti-DNA antibodies) in patients with rheumatoid arthritis treated with etanercept or combination therapy. Methods: Eight patients treated with etanercept 25 mg twice weekly were studied for a period of 85 weeks. A control group of 39 patients with rheumatoid arthritis undergoing combination treatment (methotrexate (MTX) + cyclosporin A or MTX + chloroquine) were studied for the same period of time. The occurrence of anticardiolipin antibodies (ACA-IgG) and anti-DNA was examined, together with the possible occurrence of infections due to bacteria capable of inducing B cell activation. Results: In 5/8 patients receiving etanercept an increase of ACA-IgG was seen, while anti-DNA became positive in 3/8 patients. A nasal or bronchial infection due to Staphylococcus aureus (Staph aureus) or a urinary tract infection due to E coli, occurred in all five cases. Antibiotic treatment produced a return to normal of ACA-IgG, and also of anti-DNA, in all cases except one. The infectious agent was eradicated in all subjects but one. In the control group Staph aureus was found in the nasal swab in 10/39 subjects; ACA-IgM (followed by ACA-IgG) appeared at the same time as infection occurred in 6/10, while no infection related to the increased ACA-IgM was recorded in the other four. Conclusions: Bacterial DNA, especially that enriched in CpG motifs, is a powerful immunostimulant that may, in some cases, lead to ACA or anti-DNA positivity, once tumour necrosis factor α is blocked. Eradication of the infections leads to a rapid decrease of ACA-IgG and of anti-DNA levels.

To evaluate avidity of IgG anti-beta 2-glycoprotein I antibodies (anti-beta2-GPI) in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) in relation to thrombosis, and to demonstrate a possible affinity maturation of IgG anti-beta 2-GPI during the disease course. 64 sera from 32 patients (18 with primary or secondary APS, 14 with SLE without APS) and their respective IgG fractions or affinity purified anti-beta 2-GPI were studied by anticardiolipin (aCL) and anti-beta 2-GPI enzyme linked immunosorbent assay and by chaotropic assay. Six, 12, and 14 patients had high, low, and heterogeneous avidity IgG anti-beta 2-GPI, respectively. In 12 patients an increase in antibody avidity was observed over a period of between four and 12 years. More patients with APS were in the high avidity than in the low avidity anti-beta 2-GPI group, while the opposite was observed for SLE alone (both p<0.05). The most common clinical feature among patients with high avidity anti-beta 2-GPI was thrombosis, mainly venous thrombosis (p<0.05 and p<0.02, respectively, v the low avidity anti-beta 2-GPI group). Patients with APS with or without SLE may have anti-beta2-GPI of high, low, or heterogeneous avidity. High avidity anti-beta 2-GPI appear to be associated with thrombosis and APS, while in pure SLE low avidity anti-beta 2-GPI may prevail. Monitoring of avidity may help elucidate the role of anti-beta 2-GPI affinity maturation in the pathogenesis of APS.

Antiphospholipid syndrome, a disorder characterized by pregnancy morbidity and thrombosis in young individuals, is diagnosed by detection of anticardiolipin antibodies or lupus anticoagulant using laboratory tests. As discussed in this review, correct identification of patients with this syndrome is important as prophylactic anticoagulant therapy can prevent recurrent thrombosis and reduce complications during pregnancy. Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent vascular thrombosis and pregnancy losses. Laboratory diagnosis of APS relies on the demonstration of a positive anticardiolipin antibody test by an in-house or commercially available enzyme-linked immunosorbent assay, or on the presence of lupus anticoagulant by a coagulation-based test. Persistence of the positive results must be demonstrated, and other causes and underlying factors considered. Although it is universally recognized that the routine screening tests (anticardiolipin antibody or lupus anticoagulant) might miss some cases of APS, careful differential diagnosis and repeat testing are mandatory before the diagnosis of 'seronegative APS' can be made. Correct identification of patients with APS is important because prophylactic anticoagulant therapy can prevent thrombosis from recurring and treatment of affected women during pregnancy can improve fetal and maternal outcome. Key Points Antiphospholipid syndrome (APS) is the most common acquired thrombophilia Venous and arterial thrombosis in young individuals, and pregnancy morbidity, are the hallmarks of the disease In the clinical setting, testing for both anticardiolipin antibodies and lupus anticoagulant is essential for the diagnosis of APS Differential diagnoses must be considered before labelling a patient as having 'seronegative APS' Correct identification of patients with APS is important, because prophylactic anticoagulant therapy can prevent thrombosis from recurring Treatment of affected women during pregnancy can improve fetal and maternal outcomes