Antiphospholipid syndrome and infertility.

Antiphospholipid syndrome is a systemic autoimmune disease associated with obstetric complications along with vascular events affecting multiple organ systems in patients having positive titers of antiphospholipid antibodies. Eight to 20% of infertility cases have an unknown cause, part of which could be due to antiphospholipid syndrome. Although still debatable, many studies have addressed the relation between reproductive failure and antiphospholipid antibodies through the relation between antiphospholipid antibodies and unexplained infertility as well as the effect of antiphospholipid antibodies on the outcome of in vitro fertilization-embryo transfer. Few studies and cases have associated the presence of antiphospholipid antibodies with male infertility, describing morphofunctional penile abnormalities and testicular infarction. There are not enough data to support the routine practice of testing antiphospholipid antibodies in patients with infertility.

McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome.

Background The McMaster RARE-Bestpractices project group selected the catastrophic antiphospholipid syndrome (CAPS) for a pilot exercise in guideline development for a rare disease. Objectives The objectives of this exercise were to provide a proof of principle that guidelines can be developed for rare diseases and assist in clinical decision making for CAPS. Patients/Methods The GIN-McMaster Guideline Development checklist and GRADE methodology were followed throughout the guideline process. The CAPS guideline was coordinated by a steering committee, and the guideline panel was formed with representation from all relevant stakeholder groups. Systematic reviews were performed for the key questions. To supplement the published evidence, we piloted novel methods, including use of an expert-based evidence elicitation process and ad hoc analysis of registry data. Results This paper describes the CAPS guideline recommendations, including evidence appraisal and discussion of special circumstances and implementation barriers identified by the panel. Many of these recommendations are conditional, because of subgroup considerations in this heterogeneous disease, as well as variability in patient values and preferences. Conclusions The CAPS clinical practice guideline initiative met the objective of the successful development of a clinical practice guideline in a rare disease using GRADE methodology. We expect that clinicians caring for patients with suspected CAPS will find the guideline useful in assisting with diagnosis and management of this rare disease.

Study of Flare Assessment in Systemic Lupus Erythematosus Based on Paper Patients.

OBJECTIVE: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. METHODS: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity. RESULTS: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features. CONCLUSION: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved.

McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome

Background The McMaster RARE-Bestpractices project group selected the catastrophic antiphospholipid syndrome (CAPS) for a pilot exercise in guideline development for a rare disease. Objectives The objectives of this exercise were to provide a proof of principle that guidelines can be developed for rare diseases and assist in clinical decision making for CAPS. Patients/Methods The GIN-McMaster Guideline Development checklist and GRADE methodology were followed throughout the guideline process. The CAPS guideline was coordinated by a steering committee, and the guideline panel was formed with representation from all relevant stakeholder groups. Systematic reviews were performed for the key questions. To supplement the published evidence, we piloted novel methods, including use of an expert-based evidence elicitation process and ad hoc analysis of registry data. Results This paper describes the CAPS guideline recommendations, including evidence appraisal and discussion of special circumstances and implementation barriers identified by the panel. Many of these recommendations are conditional, because of subgroup considerations in this heterogeneous disease, as well as variability in patient values and preferences. Conclusions The CAPS clinical practice guideline initiative met the objective of the successful development of a clinical practice guideline in a rare disease using GRADE methodology. We expect that clinicians caring for patients with suspected CAPS will find the guideline useful in assisting with diagnosis and management of this rare disease.

The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

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.

Rivaroxaban limits complement activation compared with warfarin in antiphospholipid syndrome patients with venous thromboembolism.

Essentials Complement activation has a pathogenic role in thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Complement activation markers were elevated in anticoagulated thrombotic APS patients. Complement activation decreased in APS patients switching from warfarin to rivaroxaban. SUMMARY: Background Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared with warfarin in APS patients with previous venous thromboembolism (VTE). Methods A total of 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomization in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex [SC5b-9] and Bb fragment) were assessed. Results APS patients had significantly higher complement activation markers compared with NC at both time-points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomized to rivaroxaban, C3a, C5a and SC5b-9 were lower at day 42 (median (ng mL-1 ) [confidence interval] 64 [29-125] vs. 83 [35-147], 9 [2-15] vs. 12 [4-18] and 171 [56-245] vs. 201 [66-350], respectively) but levels of Bb fragment were unchanged. There were no correlations between rivaroxaban levels and complement activation markers. Conclusions APS patients with previous VTE on warfarin exhibit increased complement activation, which is likely to occur via the classical pathway and is decreased by rivaroxaban administration. Rivaroxaban may therefore potentially provide an additional benefit to its anticoagulant effect in this patient group by limiting complement activation.

Antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by the occurrence of thrombosis (arterial and/or venous), often multiple, and/or pregnancy morbidity. Thrombosis is one of the major disease mechanisms, mainly caused by activating endothelial cells, monocytes, and platelets. At present, the management of APS patients with a history of thrombosis is based on long-term antithrombotic therapy, due to the high rate of recurrent thrombosis (29% per year without treatment). Obstetrical APS includes heterogeneous pregnancy complications whose pathogenesis has been increasingly elucidated in the past years. This is due to the current management and treatment, as 80% of APS patients achieve a live birth. The standard approach of APS is not supported by extensive evidence and the best options for refractory and incomplete cases need to be clarified. New and promising molecules are under investigation.

Autoantibodies to domain 1 of beta 2 glycoprotein I determined using a novel chemiluminescence immunoassay demonstrate association with thrombosis in patients with antiphospholipid syndrome.

INTRODUCTION: Antibodies to the domain 1 of beta 2 glycoprotein I (ß2GPI-D1) have been suggested as a risk marker for thrombosis in patients with the antiphospholipid syndrome (APS). This cross-sectional study aimed to analyze the clinical utility of a novel chemiluminescence assay for the detection of anti-ß2GPI-D1 antibodies. PATIENTS AND METHODS: Sera collected from patients with primary or secondary APS (n = 106; 72 with and 34 without history of thrombosis) and controls (n = 272) were tested for anti-ß2GPI-D1 IgG by chemiluminescence assay (QUANTA Flash) and by two anti-ß2GPI IgG assays (QUANTA Lite and QUANTA Flash ß2GPI IgG). RESULTS: Anti-ß2GPI-D1 IgG titers were significantly higher in patients with thrombosis (P = 0.0032) than those without. At the cut-off of 20 units, which yielded a 99.5% specificity, 24 of 72 (34.9%) patients with thrombosis and four of 34 (11.8%) without thrombosis were anti-ß2GPI-D1 IgG positive (odds ratio, OR = 4.0). By further optimizing the cut-off specifically for correlation with thrombosis, 20.8% of the patients with thrombosis and 2.9% of the patients without thrombosis were positive (OR = 8.7). The ORs were significantly lower for antibodies to the full-length ß2GPI by either the chemiluminescence assay or ELISA. Using the anti-ß2GPI chemiluminescence assay, the OR was 2.3 (recommended cut-off of 20 CU) or 4.1 (optimal cut-off 164.6 CU). Using the anti-ß2GPI ELISA, the OR was 2.7 (recommended cut-off of 20 units) or 3.7 (optimal cut-off 7.6 units). CONCLUSION: These data indicate that anti-ß2GPI-D1 IgG are present more frequently and in higher titers in APS patients with thrombotic complications than in those without.The novel ß2GPI-D1 chemiluminescence assay appears to be superior to full-length ß2GPI assays for the risk assessment of thrombotic events in APS patients.

Hughes syndrome and epilepsy: when to test for antiphospholipid antibodies?

Epilepsy and seizures are reported among the neurological manifestations of antiphospholipid syndrome (APS) at a prevalence rate of approximately 8%, which is nearly 10 times the prevalence of epilepsy in the general population. The association of seizures with antiphospholipid antibodies (aPL) is even more significant in the presence of systemic lupus erythematosus (SLE). In this review, we discuss the epidemiological, pathophysiological, laboratory, clinical, and radiological aspects of this association, and derive suggestions on when to consider testing for aPL in epileptic patients and how to manage seizures secondary to APS based on literature data. Epilepsy due to APS should be considered in young patients presenting with seizures of unknown origin. Temporal lobe epilepsy seems to be particularly prevalent in APS patients. The pathogenesis is complex and may not only involve micro-thrombosis, but also a possible immune-mediated neuronal damage. Patients with seizures and positive aPL tend to develop thrombocytopenia and livedo racemosa more frequently compared with those without aPL. Magnetic resonance imaging (MRI) remains the imaging modality of choice in these patients. The presence of SLE and the presence of neurological symptoms significantly correlate with the presence of white matter changes on MRI. In contrast, the correlation between aPL positivity and the presence of white matter changes is very weak. Furthermore, MRI can be normal in more than 30-40% of neuropsychiatric lupus patients with or without aPL. aPL testing is recommended in young patients presenting with atypical seizures and multiple hyper-intensity lesions on brain MRI in the absence of other possible conditions. New MRI techniques can better understand the pathology of brain damage in neuro-APS. The therapeutic management of epileptic APS patients relies on anti-epileptic treatment and anticoagulant agents when there is evidence of a thrombotic event. In the absence of consensual recommendations, the decision of lifelong anticoagulation is discussed on a case-by-case basis. The anti-thrombotic benefit of hydroxychloroquine and statins is supported by several studies.

Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort.

OBJECTIVE: To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up. METHODS: The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used. RESULTS: 31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors. CONCLUSIONS: In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.

Musculoskeletal manifestations of the antiphospholipid syndrome.

The scope of clinical and laboratory manifestations of the antiphospholipid syndrome (APS) has increased dramatically since its discovery in 1983, where any organ system can be involved. Musculoskeletal complications are consistently reported in APS patients, not only causing morbidity and mortality, but also affecting their quality of life. We reviewed all English papers on APS involvement in the musculoskeletal system using Google Scholar and Pubmed; all reports are summarized in a table in this review. The spectrum of manifestations includes arthralgia/arthritis, avascular necrosis of bone, bone marrow necrosis, complex regional pain syndrome type-1, muscle infarction, non-traumatic fractures, and osteoporosis. Some of these manifestations were reported in good quality studies, some of which showed an association between aPL-positivity and the occurrence of these manifestations, while others were merely described in case reports.

Autoimmune congenital heart block: complex and unusual situations.

Autoimmune congenital heart block (ACHB) is an immune-mediated cardiac disease included among the manifestations collectively referred to as neonatal lupus. The placental transference of maternal Ro/La autoantibodies may damage the conduction tissues during fetal development leading to blocking of signal conduction at the atrioventricular (AV) node in an otherwise structurally normal heart. Irreversible complete AV block is the main cardiac manifestation of ACHB, but some babies may develop endocardial fibroelastosis, valvular insufficiency, and/or frank cardiomyopathies with significantly reduced cardiac function requiring transplant. The severity of ACHB is illustrated by a global mortality rate of 20% and pacemaker rates of at least 64%, often within the first year of life. This review analyses the main complex and/or unusual clinical situations associated with ACHB, including unusual maternal immunological profiles, infrequent maternal autoimmune diseases, cardiac damage unrelated to AV block, fetal invasive management, late complications after birth, risk of congenital heart block (CHB) in ovodonation and in vitro fertilization techniques, the role of maternal features other than autoimmunity, the influence of the birth order or the risk of CHB in twins and triplets.

The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies.

BACKGROUND: Antiphospholipid syndrome is defined by the combination of thrombotic events and/or obstetric morbidity in patients who have tested positive persistently for antiphospholipid antibodies. With good treatment, approximately 70% of pregnant women with antiphospholipid syndrome will deliver a viable live infant. However, current management does not prevent all maternal, fetal, and neonatal complications of antiphospholipid syndrome. OBJECTIVES: This observational, retrospective, single-center cohort study aimed to assess pregnancy outcome in women with antiphospholipid antibodies who were treated with hydroxychloroquine in addition to conventional treatment during pregnancy. STUDY DESIGN: One-hundred seventy pregnancies in 96 women with persistent antiphospholipid antibodies were analyzed: (1) 51 pregnancies that occurred in 31 women were treated with hydroxychloroquine for at least 6 months before pregnancy, and the therapy continued throughout gestation (group A); (2) 119 pregnancies that occurred in 65 women with antiphospholipid antibodies that were not treated with hydroxychloroquine were included as controls (group B). RESULTS: Hydroxychloroquine-treatment was associated with a higher rate of live births (67% group A vs 57% group B; P = .05) and a lower prevalence of antiphospholipid antibodies-related pregnancy morbidity (47% group A vs 63% B; P = .004). The association of hydroxychloroquine with a lower rate of any complication in pregnancy was confirmed after multivariate analysis (odds ratio, 2.2; 95% confidence interval, 1.2-136; P = .04). Fetal losses at >10 weeks of gestation (2% vs 11%; P = .05) and placenta-mediated complications (2% vs 11%; P = .05) were less frequent in group A than group B. Pregnancy duration was longer in group A than group B (27.6 [6-40] vs 21.5 [6-40] weeks; P = .03). There was a higher rate of spontaneous vaginal labor in hydroxychloroquine-treated women compared with group B (37.3% vs 14.3%; P = .01). CONCLUSIONS: Despite the heterogeneity in the 2 groups in terms of systemic lupus erythematosus prevalence and previous pregnancy history, our results support the concept that women with antiphospholipid antibodies may benefit from treatment with hydroxychloroquine during pregnancy to improve pregnancy outcome. The addition of hydroxychloroquine to conventional treatment is worthy of further assessment in a proper designed randomized controlled trial.

Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE.

INTRODUCTION: The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. AIMS: The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. METHODS: Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. DISCUSSION: If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5.

Anti-C1q antibodies in systemic lupus erythematosus.

OBJECTIVE: Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. METHODS: Information and blood samples were obtained in a cross-sectional study from patients with SLE (n = 308) and other rheumatologic diseases (n = 389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA. RESULTS: Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR = 2.7, 95% CI: 1.8-4, p < 0.001). Anti-C1q was associated with proteinuria (OR = 3.0, 95% CI: 1.7-5.1, p < 0.001), red cell casts (OR = 2.6, 95% CI: 1.2-5.4, p = 0.015), anti-dsDNA (OR = 3.4, 95% CI: 1.9-6.1, p < 0.001) and anti-Smith (OR = 2.8, 95% CI: 1.5-5.0, p = 0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR = 2.3, 95% CI: 1.3-4.2, p < 0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR = 14.9, 95% CI: 5.8-38.4, p < 0.01). CONCLUSIONS: Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis.

Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients.

OBJECTIVES: To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. METHODS: In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. RESULTS: 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. CONCLUSIONS: Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.

Changes in quality of life in the first 5 years of disease in a multicenter cohort of patients with systemic lupus erythematosus.

OBJECTIVE: The Medical Outcomes Study Short Form 36 (SF-36) is recommended to assess quality of life (QOL) in systemic lupus erythematosus (SLE). The aim of the current study was to assess QOL over time in the first 5 years of a multicenter inception cohort of patients with SLE. METHODS: An inception SLE cohort was assembled according to a standardized protocol between 2000 and 2012. In addition to clinical and laboratory assessments, patients completed the SF-36 at yearly intervals. Only patients who had ≥5 completed QOL questionnaires were included in these analyses. Generalized estimating equation models were run separately for each of the 8 subscales and for the physical and mental component summary scores, adjusting for repeated measures by patients. RESULTS: A total of 495 patients were included. The mean ± SD disease duration at the first visit was 5.3 ± 4.1 months. The mean ± SD age at enrollment was 35.8 ± 13.2 years. All 8 subscales and the 2 summary scores showed improvement in the first 2 years from enrollment. Between years 2 and 5, none of the subscales or summary scores showed any change. Minimum clinically important improvement was achieved by 35-56% of the patients and was influenced by demographic and disease factors. CONCLUSION: Unlike late-stage lupus, where QOL is stable over time, in patients with early disease, all subscales improve in early followup up to 2 years. Therefore, the SF-36 may be a sensitive outcome measure in early disease in patients with SLE.

Patterns of systemic lupus erythematosus expression in Europe.

OBJECTIVES: To analyse the differences in disease expression of European SLE patients based on gender, age at diagnosis, and ethnicity. METHODS: A two-year, retrospective, multicentre, observational study was carried out in five countries (France, Germany, Italy, Spain and the UK). Patients' clinical manifestations including disease activity, organ involvement, organ damage and flares were analysed. RESULTS: Thirty-one centres enrolled 412 consecutive eligible patients (90.5% of women), with active disease, stratified by disease severity (half severe and half non-severe). Baseline characteristics included; mean (SD) age: 43.3 (13.6) years, SLE duration: 10.7 (8.0) years and age at disease diagnosis: 32.6 (13.0) years old. The mean (SD) SELENA-SLEDAI and SLICC/ACR scores were: 8.1 (6.7) and 0.82 (1.36), respectively. Over half of patients experienced flares (54.9%). The average number of annual flares was 1.01 (0.71) flares/year. In males compared to females, the renal system was more frequently active (53.8% vs 30.0%, p=0.002), the mean SLICC/ACR score was higher (1.15 vs 0.79, p=0.039) and the pulmonary system was more likely to be damaged (12.8% vs 3.8%, p=0.010). Furthermore, patients diagnosed at younger age displayed more renal system activity (young: 56.3% vs adult: 33.4% vs elder: 8.9%, p<0.001) and renal damage (25.0% vs 6.9% vs 2.2%, p=0.018) compared to the others. The annual number of flares (1.13 vs 1.05 vs 0.81 flares/year, p<0.0001), including the occurrence of severe flares (0.58 vs 0.51 vs 0.20, p<0.0001), was also higher in these patients. Conversely, greater organ damage was observed in patients diagnosed at an older age compared to the others. The mean SLICC/ACR score was higher (1.31 vs young: 0.88 and adult: 0.78, p<0.001) in patients diagnosed in the older age groups. The pulmonary (13.3% vs younger: 0% vs adult: 3.7%, p=0.030) and cardiovascular (17.8% vs younger: 0% vs adult: 2.9%, p<0.001) systems were more frequently damaged in these patients. Black African descents showed greater disease activity compared to Caucasian patients. They flared more often (77.1% vs 48.6%, p=0.001) and experienced a greater number of annual flares (1.57 vs 0.89 flares/year, p<0.0001), mainly more severe flares (0.89 vs 0.38/year, p<0.0001). They also were more likely to experience renal system damage. CONCLUSION: The study showed clearly two patient subsets. The disease was the most active in Black African descents, and this phenomenon has never been described before in continental Europe. The disease was also more active in patients diagnosed at a younger or adult. Greater disease damage was observed in males and in patients diagnosed at an older age.