EULAR Recommendations for Women's Health and the Management of Family Planning, Assisted Reproduction, Pregnancy and Menopause in Patients with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

Lupus Myelopathy in a Child

A 5-year-old female developed, after a 7-month period of fever, anorexia, weight loss, and a transitory cutaneous erythematous eruption, a severe acute transverse myelopathy, with a partial recovery of motor and sensory function. She had positive antinuclear and antidouble-stranded DNA antibodies but no antiphospholipid antibodies. Six months later she had massive proteinuria and restarted treatment with steroids and cyclophosphamide. Our patient is one of the youngest reported with lupus myelopathy. We discuss the clinical presentation, the magnetic resonance imaging findings, and other relevant laboratory studies of this rare but serious complication of systemic lupus erythematosus.

Gravidez e Anticorpos Antifosfolípidos em Doentes com Lúpus Eritematoso Sistémico. Uma Avaliação do Prognóstico

Introdução e Objectivo: A presença de anticorpos antifosfolípidos (AAF) está associada a perdas embrionárias e fetais e a outras complicações obstétricas como pré-eclâmpsia, restrição de crescimento intra-uterino e parto pré-termo. Os doentes com lúpus eritematoso sistémico (LES) com frequência possuem AAF e síndroma antifosfolípidica (SAAF) secundária. O objectivo deste estudo é avaliar comparativamente o prognóstico da gravidez em mulheres com LES na presença e na ausência de AAF. Material e Métodos:Avaliação retrospectiva de 136 gestações em mulheres com diagnóstico prévio de LES cujo seguimento foi realizado na nossa instituição entre 1993 e 2007. As grávidas com e sem AAF foram consideradas separadamente. Dados relativos a idade materna, história obstétrica passada, actividade do LES no início da gravidez, existência de nefropatia, evolução da gravidez actual, idade gestacional no parto, tipo de parto, peso do recém-nascido e a existência de complicações hipertensivas na gravidez foram analisados. Resultados: 28% (38) das grávidas com LES apresentavam AAF. Deste grupo, 28,9% tinham história de perdas fetais do segundo e/ou terceiro trimestre, em oposição a 6,12% nas doentes sem AAF(p<0,05). A avaliação da actual gravidez demonstrou uma taxa de insucesso na gravidez significativamente mais elevada na população com AAF(8,1% versus 2,1%, p<0,05). Não se verificaram diferenças significativas no peso médio do recém-nascido e na taxa de restrição intra-uterina em função da presença de AAF. A idade gestacional media no parto foi de 36,9 semanas em ambos os grupos com uma taxa idêntica de parto pré-termo. O parto ocorreu por cesariana em 47% das doentes com AAF e em 44,1% das doentes sem AAF. Conclusões:Os antecedentes obstétricos de perda fetal do 2º e 3º trimestre e a probabilidade de aborto espontâneo são mais frequentes em grávidas com LES e AAF. Nos restantes parâmetros analisados não se verificaram diferenças significativas em função da presença de AAF.

Acquired-Transient Factor X Deficiency in a Teenager with Extensive Burns

Acquired factor X deficiency is an extremely rare situation. It has shown to be associated with systemic amyloidosis, respiratory mycoplasma infection, factor X inhibitors, antiphospholipid antibodies, vitamin K defi ciency/liver disease as well as the use of certain medications (meropenem, valproic acid). The pathogenesis and transient nature of this deficit remain poorly understood. The authors describe the case of a teenager hospitalised for extensive burns that developed active bleeding after removal of central venous catheter. He was diagnosed with transient factor X deficiency. Normalisation of coagulation status and factor X levels occurred spontaneously 10 days after the bleeding episode.

Primary Antiphospholipid Syndrome: Pregnancy Outcome in a Portuguese Population

Introduction:Women with antiphospholipid syndrome(APS) may suffer from recurrent miscarriage, fetal death, fetal growth restriction (FGR), pre-eclampsia, placental abruption, premature delivery and thrombosis. Treatment with aspirin and low molecular weight heparin (LMWH) combined with close maternal-fetal surveillance can change these outcomes. Objective: To assess maternal and perinatal outcome in a cohort of Portuguese women with primary APS. Patients and Methods: A retrospective analysis of 51 women with primary APS followed in our institution (January 1994 to December 2007). Forty one(80.4%) had past pregnancy morbidity and 35.3%(n=18) suffered previous thrombotic events. In their past they had a total of 116 pregnancies of which only 13.79 % resulted in live births. Forty four patients had positive anticardiolipin antibodies and 33 lupus anticoagulant. All women received treatment with low dose aspirin and LMWH. Results: There were a total of 67 gestations (66 single and one multiple). The live birth rate was 85.1%(57/67) with 10 pregnancy failures: seven in the first and second trimesters, one late fetal death and two medical terminations of pregnancy (one APS related). Mean (± SD) birth weight was 2837 ± 812 g and mean gestational age 37 ± 3.3 weeks. There were nine cases of FGR and 13 hypertensive complications(4 HELLP syndromes). 54.4% of the patients delivered by caesarean section. Conclusions: In our cohort, early treatment with aspirin and LMWH combined with close maternal-fetal surveillance was associated with a very high chance of a live newborn.

Influence of Apolipoprotein E Plasma Levels and Tobacco Smoking on the Induction of Neutralising Antibodies to Interferon-Beta

Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated with the development of NAbs. Thirty-one female MS patients treated with subcutaneously administered IFN-beta were included. Demographic and clinical characteristics were compared between NAbs response groups using t tests for continuous and logistic regression analysis and Fisher's exact tests for categorical data, respectively. Multivariate logistic regression was used to evaluate the effect of potential confounders. Patients who developed NAbs had lower apoE levels before treatment, 67 (47-74) mg/L median (interquartile range), and at the moment of NAb analysis, 53 (50-84) mg/L, in comparison to those who remained NAb-negative, 83 (68-107) mg/L, P = 0.03, and 76 (66-87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a one-standard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04-0.77), P = 0.04. When adjusting for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta.

Specificity and Sensitivity of Screening for Anti-HLA Antibodies in Kidney Allograft Dysfunction

BACKGROUND: Prospective testing for posttransplant circulating anti-HLA antibodies seems to be a critical noninvasive tool, but confirmatory data are lacking. MATERIALS AND METHODS: Over the last 3 years, peritubular capillary (PTC) C4d deposition was prospectively sought by an immunofluorescence technique applied to frozen tissue in biopsies obtained for allograft dysfunction. Screening for circulating anti-HLA class I/II alloantibodies (AlloAb) by the flow cytometric test was performed simultaneously. RESULTS: We evaluated 132 sets of biopsies and simultaneous serum samples. PTC C4d deposition was demonstrated in 15.9% (21/132) of biopsies. Circulating anti-HLA I/II AlloAb were detected in 25% (33/132) of serum samples. Employing receiver-operator characteristic (ROC) curves for all C4d-positive biopsies, screening for AlloAb showed a global specificity of 82% and sensitivity of 61.9%. When this analysis was restricted to biopsies obtained in the first month posttransplantation, the sensitivity increased to 81.8%, but the specificity decreased to 76.9%. After the first month posttransplantation, we observed sensitivity of 40.0% and a specificity of 86.4%. In the first month posttransplantation, all patients with a diagnosis of acute antibody-mediated rejection displayed circulating anti-HLA class I/II, but not always at the same time as the C4d-positive biopsy. CONCLUSIONS: In the first month posttransplantation, prospective monitoring of anti-HLA antibodies may be useful. The high sensitivity allows the identification of patients at risk, affording an earlier diagnosis of antibody-mediated rejection. After the first month, the test can be used to evaluate allograft dysfunction episodes, since positivity is highly suggestive of an antibody-mediated process.

De Novo Hypertension and Decline of Renal Function in a Young Woman with Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Antiphospholipid syndrome nephropathy and lupus nephritis have similar clinical and laboratory manifestations and achieving the accuracy of diagnosis required for correct treatment frequently necessitates a kidney biopsy. We report the case of a 29-year-old woman referred to the nephrology service for de novo hypertension, decline of renal function and proteinuria. She had had systemic lupus erythematosus and antiphospholipid syndrome since the age of 21 and was taking oral anticoagulation. Two weeks later, after treatment of hypertension and achievement of adequate coagulation parameters, a percutaneous renal biopsy was performed. The biopsy revealed chronic lesions of focal cortical atrophy, arterial fibrous intimal hyperplasia and arterial thromboses, which are typical features of antiphospholipid syndrome nephropathy. We describe the clinical manifestations and histopathology of antiphospholipid syndrome nephropathy and review the literature on renal biopsy in patients receiving anticoagulation.

Leg Ulcers in Antiphospholipid Syndrome Secondary to Systemic Lupus Erythematosus Treated with Intravenous Immunoglobulin

BACKGROUND: Despite encouraging reports on the efficacy of intravenous immunoglobulin (IVIg) in antiphospholipid syndrome, 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. OBSERVATION: We describe the significant improvement of leg ulcers with IVIg in a 61-year-old female, with diabetes mellitus, venous peripherical insufficiency and secondary antiphospholipid syndrome to systemic lupus erythematosus. CONCLUSIONS: This case illustrates a rare cause of leg ulcers and documents that IVIg may be an effective adjuvant treatment in the management of selected patients with antiphospholipid syndrome when conventional strategies using subcutaneous heparin and low-dose aspirin are insufficient.

Anti-Phospholipase A2 Receptor Antibodies in the Diagnosis of Idiopathic Membranous Nephropathy

Circulating anti-phospholipase A2 receptor antibodies (anti-PLA2R) have been described in 70% to 80% of the patients with idiopathic membranous nephropathy (iMN), but not in patients with secondary membranous nephropathy or other glomerular diseases. The goal of this study was to evaluate the sensitivity and specificity of the assay for anti-PLA2R in the diagnosis of iMN. Anti-PLA2R IgG, Elisa and immunofluorescence tests were used to detect circulating anti-PLA2R. These tests were applied in 53 patients who had a kidney biopsy. Of these, 38 had histological diagnosis of membranous nephropathy (MN) and the remaining had other glomerular diseases. The MN was classified as idiopathic in 33 patients after clinical exclusion of secondary causes. Anti-PLA2R were positive in 57.6% of the patients with iMN. All patients with secondary membranous nephropathy or other glomerular diseases did not show circulating anti-PLA2R. The sensitivity was 57.6% (CI 39.2-74.5) and specificity 100% (CI 47.8-100), AUC 0.788; p < 0.0001 for the detection of iMN. 71.4% of the iMN patients that tested negative for anti-PLA2R were in partial or complete remission. The detection of anti-PLA2R in the studied population had a specificity of 100% for the iMN diagnosis. Prior treatments seem to make the test negative and contribute to a lower sensitivity.

Anti-N-methyl-D-Aspartate Receptor Encephalitis with Positive Serum Antithyroid Antibodies, IgM Antibodies Against Mycoplasma Pneumoniae and Human Herpesvirus 7 PCR in the CSF

We report the case of a boy with an encephalopathy associated with extrapyramidal and psychiatric symptoms and anti-N-methyl-D-aspartate receptor antibodies. He had positive serum antithyroid antibodies, IgM antibodies against Mycoplasma pneumoniae and human herpesvirus 7 polymerase chain reaction in the cerebrospinal fluid. He was successfully treated with rituximab, after steroids, intravenous immunoglobulin and plasma exchange. The pathophysiology of this disorder may be post-infectious and autoimmune.

The Burkholderia Cenocepacia OmpA-Like Protein BCAL2958: Identification, Characterization, and Detection of Anti-BCAL2958 Antibodies in Serum from B. Cepacia Complex-Infected Cystic Fibrosis Patients

Respiratory infections by bacteria of the Burkholderia cepacia complex (Bcc) remain an important cause of morbidity and mortality among cystic fibrosis patients, highlighting the need for novel therapeutic strategies. In the present work we have studied the B. cenocepacia protein BCAL2958, a member of the OmpA-like family of proteins, demonstrated as highly immunogenic in other pathogens and capable of eliciting strong host immune responses. The encoding gene was cloned and the protein, produced as a 6× His-tagged derivative, was used to produce polyclonal antibodies. Bioinformatics analyses led to the identification of sequences encoding proteins with a similarity higher than 96 % to BCAL2958 in all the publicly available Bcc genomes. Furthermore, using the antibody it was experimentally demonstrated that this protein is produced by all the 12 analyzed strains from 7 Bcc species. In addition, results are also presented showing the presence of anti-BCAL2958 antibodies in sera from cystic fibrosis patients with a clinical record of respiratory infection by Bcc, and the ability of the purified protein to in vitro stimulate neutrophils. The widespread production of the protein by Bcc members, together with its ability to stimulate the immune system and the detection of circulating antibodies in patients with a documented record of Bcc infection strongly suggest that the protein is a potential candidate for usage in preventive therapies of infections by Bcc.