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The current treatment to prevent pregnancy morbidity (PM) associated with antiphospholipid antibodies (aPL) is based on the use of low dose aspirin and low molecular weight heparin (henceforth defined as standard of care (SoC) treatment). Despite the SoC, up to 30% of women with aPL continue to have pregnancy complications. The global antiphospholipid syndrome (APS) score (GAPSS) is a tool to quantify the risk for the aPL-related clinical manifestations. In this study, we investigated the individual clinical response to SoC in women with aPL after stratifying them according to their GAPSS.One-hundred-fourty-three women (352 pregnancies) with aPL ever pregnant treated with SoC therapy were included. The patients GAPSS was then grouped according to the patients' GAPSS into low risk (6), medium risk (6-11), and high risk (≥12).The live birth rate was 70.5% (248 out of the 352 pregnancies), 45 patients (31%) experienced at least one event of PM, defined as early or late. Patients were stratified according to GAPSS values, in order to identify a low risk group (GAPSS6, n = 72), a medium risk group (GAPSS 6-11, n = 66) and a high risk group (GAPSS ≥12, n = 5). When considering patients who ever experienced any PM while treated with SoC, all patients in the high risk group experienced PM, while patients in the medium group had a significant higher rate of PM when compared to the low risk group [29 (43.9%) patients V.s. 11 (15.3%), respectively; p0.001]. When analysing the number of pregnancies in the three groups, patients in the high risk group had significantly lower live birth rates, when compared to the other groups [11 (40.7%) live births vs. 100 (62.1%) and 137 (82.5%), respectively; p0.05]. Furthermore, patients with medium risk group also had significantly lower live birth rates, when compared to the lower risk group (p0.001).GAPSS might be a valuable tool for to identify patients with a higher likelihood of response to SoC.

Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) - a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end-organ damage. To date, carfilzomib-associated TMA has predominantly been described in relapsed/refractory myeloma patients. We report eight patients with newly diagnosed myeloma who experienced TMA events while receiving carfilzomib on the phase II CARDAMON trial. The first three occurred during maintenance single-agent carfilzomib, two occurred at induction with carfilzomib given with cyclophosphamide and dexamethasone (KCd) and three occurred during KCd consolidation. At TMA presentation 6/8 were hypertensive; 7/8 had acute kidney injury and in three, renal impairment persisted after resolution of TMA in other respects. The mechanism of carfilzomib-associated TMA remains unclear, though patients with known hypertension seem particularly susceptible. Given the first three cases occurred during maintenance after a longer than five-week treatment break, a protocol amendment was instituted with: aggressive hypertension management, carfilzomib step-up dosing (20 mg/m2 on day 1) at start of maintenance before dose escalation to 56 mg/m2 maximum, and adding 10 mg dexamethasone as premedication to maintenance carfilzomib infusions. No further TMA events occurred during maintenance following this amendment and the TMA incidence reduced from 4·2 to 1·6 per 1 000 patient cycles.

The management of lupus nephritis (LN) and concomitant thrombotic microangiopathy (TMA), with or without antiphospholipid antibodies (aPL), remains controversial, and few studies are available to inform clinical management.1–4 The purpose of this multicentre retrospective study was to analyse the impact of anticoagulation (vitamin K antagonists (VKAs) and/or heparins) in addition to conventional immunosuppression on kidney outcomes (assessed at 12 months, according to the Kidney Disease: Improving Global Outcomes-KDIGOguidelines5) in patients with biopsy-proven LN and concomitant TMA. Data source, population and statistical analysis are detailed in the online supplementary material 1. Anticoagulation was considered if given for at least three consecutive months after TMA diagnosis.### Supplementary data [annrheumdis-2018-214559supp002.docx] We retrospectively identified 97 patients with biopsy-proven LN and TMA (2007–2017). See online supplementary table 1 for clinical and demographic characteristics. Laboratory parameters were collected at the time of the biopsy. The mean age of patients was 38.9±15.2 years (13–69) and 85 females (87.6%). Most had proliferative LN (class …

Biological therapies represent a fundamental innovation for the management of inflammatory bowel diseases (IBD). However, many biological originators have reached, or are about to reach, patent expiry and long-term therapy costs have become progressively unsustainable. CT-P13, a biosimilar of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody infliximab, might represent a significant alternative to its originator, with the potential to decrease medical care costs and, therefore, become available to a large number of patients.In this systematic review, we analyzed the data from available clinical trials that recently investigated the validity of indication extrapolation of CT-P13 for the treatment of IBD in naïve patients and in patients who switched from its originator infliximab, focusing on clinical efficacy, safety and immunogenicity.A detailed literature search was developed a priori to identify articles that investigated the validity of indication extrapolation of CT-P13 for the treatment of IBD in TNF inhibitor treatment-naïve patients and in patients who switched from the originator infliximab. This was applied to Ovid MEDLINE, In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus for content from 2012 to September 2016.We based our review on the available data from 11 studies that included a total of 1007 IBD patients: 570 patients suffering from Crohn's disease (294 switched and 276 naïve), 435 patients suffering from ulcerative colitis (127 switched and 308 naïve), and two IBD unclassified patients (switched). Overall, no significant difference in efficacy and safety between the originator infliximab and its biosimilar CT-P13 was observed. When assessing the safety of CT-P13, we found that 9.2% of patients experienced adverse effects (4.1% infusion-related reactions and 4.3% infections).The analyzed studies did not report a significant difference in terms of efficacy, safety and immunogenicity when comparing the clinical experience with CT-P13 with the available literature data on the originator treatment in IBD. However, some debate is ongoing regarding interchangeability and immunogenicity.

Glucocorticoids (GCs) have traditionally been the center of systemic lupus erythematosus (SLE) treatment and they continue to be recommended by the EULAR and ACR as the first-line therapy for sever...

Objective: It has been documented that several major components of air pollution, including trace elements and polycyclic aromatic hydrocarbons, are associated with the prevalence of systemic lupus erythematosus (SLE). However, the impact of air pollution on the SLE disease activity is still elusive. In this paper, we review the current evidence investigating the link between air pollution, especially when measured as PM2.5, and SLE severity and activity. Methods: A detailed literature search was applied a priori to the Ovid MEDLINE In-Process and Other Non-Indexed Citation 1986 to present. Presented abstracts from the European League Against Rheumatism and American College of Rheumatology (ACR)/Association for Rheumatology Health Professionals (ARHP) Annual Meetings (2011-2018) were also screened. Results: Out of a total of 1354 papers retrieved from search and references list for detailed evaluation, data from 652 patients with SLE from three studies were analyzed. Two studies had an observational longitudinal design, counting for 348 patients with a follow-up of 24 months and 79 months. Retrieved studies differed for disease activity assessment and air pollution quantifications. Conclusion: Current evidence suggests that variations in air pollution may influence the disease activity in patients with SLE. However, the sample size, methodological biases, and differences across the studies make further research mandatory. Understanding the increased burden of SLE and its complications, not only from a medical, but also from a socio-demographic perspective, including an exposure to pollutants, should have implications for resource allocation and access to subspecialty care.

The current treatment of thrombotic APS patients includes long-term anticoagulation with oral vitamin K antagonists (VKAs), with warfarin being the one most commonly used. However, the use of VKAs can be challenging, especially in patients with APS. VKAs monitoring in patients with aPL is complicated by the heterogeneous responsiveness to LAs of reagents used in the International Normalized Ratio test, potentially resulting in instability of anticoagulation. For decades, VKAs were the only available oral anticoagulants. However, non-VKA oral anticoagulants, including a direct thrombin inhibitor (dabigatran etexilate) and direct anti-Xa inhibitors (rivaroxaban, apixaban and edoxaban), are currently available. The use of these agents may represent a major step forward since, unlike VKAs, they have few reported drug interactions and they do not interact with food or alcohol intake, thereby resulting in more stable anticoagulant intensity. Most importantly, monitoring their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this review, we discuss the clinical and laboratory aspects of non-VKA oral anticoagulants, focusing on the available evidence regarding their use in patients with APS.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with unpredictable course, intermingled with flares and periods of remission. Although the prognosis of the disease has improved in the past decades, current therapies are still associated with treatment-related complications. Recently, there has been major progress in the understanding of the pathogenesis of SLE, paving the way for the development of new biological agents, potentially revolutionizing the treatment of SLE. This review summarizes available data on novel biological therapies for SLE, focusing on recent results from clinical trials. As a result of treatment strategies based upon an individualized therapeutic approach, it is hoped that the clinical view of SLE will change from a severe autoimmune disease to a condition in which significant damage, mortality and treatment related complications can be prevented in the majority of SLE patients.

The most common neurological manifestation of antiphospholipid syndrome (APS) is ischaemic stroke. Identifying patients with APS at high risk for developing any thrombotic event remains a major challenge. In this study, the aim was to identify predictive factors of ischaemic stroke in a cohort of primary APS (PAPS) patients who presented with new onset symptoms suggestive of acute stroke.This prospective multicentre study included 36 consecutive PAPS patients who presented with new onset symptoms suggestive of an acute stroke. Patients were prospectively followed up for 12 months.In 10 (28%) out of 36 PAPS patients [mean age 41 years (SD 13.4), 70% female], the suspicion of an acute stroke was confirmed by brain magnetic resonance imaging. Sixty per cent of these patients were50 years old. Eight of the 10 patients had a history of previous venous thrombosis and were receiving vitamin K antagonist (VKA), with international normalized ratio target 2-3; one patient had a history of a previous arterial event receiving treatment with VKA target international normalized ratio 2-3 plus low dose aspirin; and one patient had a history of previous pregnancy morbidity receiving only low dose aspirin. Time in the therapeutic range for patients receiving VKA was 77.7% (SD 6.6%). Hypercholesterolaemia was significantly higher in patients with confirmed stroke compared to those without (P0.05). Similarly, a significantly higher rate of anti-β2 glycoprotein-I (β2GPI) antibodies (immunoglobulin G/immunoglobulin M; P0.05) and higher adjusted global APS score (aGAPSS) values were found in patients with a confirmed stroke [mean aGAPSS 8.9 (SD 4.7) vs. mean aGAPSS 6.4 (SD 2.5); P0.05].Patients with PAPS, including young patients, have a high risk of recurrent thrombosis despite anticoagulation treatment. A careful risk assessment is mandatory to identify patients at risk for recurrence.

The efficacy of glucocorticoids (GCs) in treating systemic lupus erythematosus (SLE) is beyond doubt. However, GCs-related adverse effects (AEs) are multiple and serious. Despite the current available evidence suggesting to reduce daily doses of prednisone7.5 mg/day, or even to withdraw it, in the real-life practice, it is not uncommon to see patients receiving medium doses (up to 30 mg/day prednisone or equivalent) or high doses (≥30 mg/day).We systematically reviewed the literature with a priori strategy, to assess the rate of AEs related to medium or high doses of GCs in patients with SLE, analyzing randomized control trials with at least one of the treatment groups including GCs alone at medium or high doses.We found a rate of 9/100 patients/year for hyperglycemias/diabetes, 25/100 patients/year for infections, and 12/100 patients/year for avascular necrosis of the hip. Interestingly, when adjusting for GC dose and treatment duration, we observed no difference in terms of AEs comparing patients receiving medium versus high doses.In the era when treat-to-target strategies have been proposed in order to control SLE disease activity, improved health-related quality of life, and reduced morbidity and mortality, using GCs in a more restrictive way should be a goal to prevent major complications in patients with SLE.

Antiphospholipid syndrome (APS) is characterized clinically by the occurrence of either venous or arterial thrombosis and/or pregnancy morbidity (recurrent miscarriages in the first trimester, or foetal death in the second or third trimesters, or severe preeclampsia necessitating delivery of a premature infant before 34 weeks of gestation).

A challenge in antiphospholipid syndrome (APS) is to translate targeted therapies from animal and in vitro models to clinical trials. The 15th International Congress on Antiphospholipid Antibodies (aPL) Task Force on Treatment Trends summarized new developments in APS targeted treatment since the 14th International Congress on aPL (September 2013). The task force also discussed additional treatments and/or pathways that can be considered in the management of aPL-positive patients.

Objective This study was performed to prospectively and independently validate the Global Antiphospholipid Syndrome Score (GAPSS), a system derived from the combination of independent risk factors for thrombosis, including antiphospholipid antibodies (aPL) and conventional cardiovascular risk factors. Methods The GAPSS was applied to 51 consecutive systemic lupus erythematosus patients, all positive for aPL and prospectively followed up for mean ± SD 32.94 ± 12.06 months. Of them, 48 were women with a mean ± SD age of 37.35 ± 12.15 years at entry. The GAPSS was calculated yearly for each patient by adding together the points corresponding to the risk factors. Results An increase in the GAPSS (entry versus last visit) was seen in patients who experienced vascular events (n = 4, mean ± SD 7.5 ± 4.36 versus 10.0 ± 5.4; P = 0.032). No changes were observed in those without thrombosis (n = 47, mean ± SD 8.28 ± 4.88 versus 7.13 ± 5.75; P = 0.24). An increase in the GAPSS during the followup was associated with a higher risk of vascular events (relative risk 12.30 [95% confidence interval (95% CI) 1.43–106.13], P = 0.004), and an increase of more than 3 points showed the best risk accuracy for vascular events (hazard ratio 48 [95% CI 6.90–333.85], P = 0.0001). The cumulative proportion of thrombosis-free individuals was lower in patients whose GAPSS was increased by 3 or more points (P = 0.0027). Conclusion We have prospectively demonstrated that GAPSS is a valid tool for accurate prediction of vascular events in SLE patients with aPL.

OBJECTIVES: The objectives of this study are to examine the efficacy and safety of low-dose aspirin (LDA) vs LDA plus low-intensity warfarin (LDA + W) in the primary thrombosis prevention of aPL-positive patients with SLE and/or obstetric morbidity and the role of clinical and serological markers in the development of thrombosis. METHODS: In this 5-year prospective, randomized, open, controlled trial, 166 patients with aPL were randomly assigned using a minimization protocol to receive treatment with LDA (n = 82) or LDA + W [international normalized ratio (INR) = 1.5] (n = 84). Sixty-six patients who declined randomization were followed up in an observational arm. Clinical and laboratory characteristics and medication side effects were recorded. RESULTS: There were no differences in the number of thromboses between patients treated with LDA (4/82) or LDA + W (4/84) [hazard ratio (HR) 1.07, 95% CI 0.27, 4.3]. The incidence of thrombosis in the randomized patients was 8/166 (1.8 events/100 person-years) (HR 1.07, 95% CI 0.27, 4.3) and in the observational arm was 7/66 (4.9 events/100 person-years) (HR 2.43, 95% CI 0.87, 6.79). Sixty-five of 66 patients included in the observational arm received LDA. None of the examined clinical or serological factors appeared to predict thrombosis. Medication side effects included mild gastrointestinal symptoms in the LDA group (n = 2) and bleeding in the LDA + W group (n = 11; 1 nasal and 10 menorrhagia). The risk difference for bleeding was 13% (CI 6, 20). CONCLUSION: No differences in the number of thromboses were observed between patients treated with LDA vs those treated with LDA + W. More episodes of bleeding were detected in the LDA + W group. The LDA + W regime was significantly less safe and not as acceptable as LDA alone. TRIAL REGISTRATION: ISRCTN81818945; http://isrctn.org/.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that results from a combination of genetic, environmental, and hormonal factors. The disease is characterized by a heterogeneous clinical presentation, a different course in different individuals, and a variability in the disease progression/fluctuations within the same patient. The clinical picture of SLE is extremely variable and may be related to disease activity, organ damage, drug toxicity, and quality of life.

Antiphospholipid syndrome (APS) is a disorder characterized by the association of arterial or venous thrombosis and/or pregnancy morbidity with the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant antibodies, and/or anti-β2-glycoprotein I antibodies). Several studies have contributed to uncovering the basis of antiphospholipid antibody pathogenicity, including the targeted cellular components, affected systems, involved receptors, intracellular pathways used, and the effector molecules that are altered in the process. Therapy for thrombosis traditionally has been based on long-term oral anticoagulation; however, bleeding complications and recurrence despite high-intensity anticoagulation can occur. Based on all the data obtained, new potential therapeutic agents have been proposed. Statins have a variety of direct effects on gene expression and the function of cells of both the innate and adaptive immune systems, many of which are related to blockade of GTPase isoprenylation. In APS, statins have multiple profound effects on monocyte, lymphocyte, and endothelial cell activities, all of which may contribute to thrombosis prevention in APS patients. Nevertheless, larger randomized trials are needed to validate the role of statins in the treatment of this autoimmune disease.

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.

We retrospectively studied a large cohort of patients with primary antiphospholipid syndrome (APS) from 4 different referral centers to analyze the clinical and serologic features and, specifically, to determine the number of patients going on to develop systemic lupus erythematosus (SLE) or other autoimmune disease after long-term follow-up. The study included 128 unselected patients with primary APS who fulfilled the Sapporo International Criteria from 4 different tertiary hospitals in the United Kingdom, Mexico, and Spain. The patients had attended the referral centers between January 1987 and July 2001. We reviewed clinical and serologic characteristics according to a pre-established protocol. We used univariate analysis with the chi-squared or Fisher exact test and logistic regression to analyze possible factors related to the coexistence of SLE and APS. Ninety-seven female and 31 male patients fulfilled the criteria, with a median age of 42 +/- 12 years (range, 16-79 yr), and with a mean follow-up of 9 +/- 3 years (range, 2-15 yr). The main manifestations included deep vein thrombosis in 62 patients (48%), arterial thrombosis in 63 (49%) patients, pregnancy loss in 177/320 (55%) cases, and pulmonary embolism in 37 (30%) patients. Other clinical manifestations were migraine in 51 (40%) patients, thrombocytopenia in 48 (38%), livedo reticularis in 47 (37%), and valvular disease in 27 (21%). Serologic findings were anticardiolipin antibodies (aCL) IgG positive in 110 (86%) patients, aCL IgM in 36 (39%), lupus anticoagulant in 71 (65%), antinuclear antibodies in 47 (37%), and positive Coombs test in 5 (4%) patients. During the follow-up and after a median disease duration of 8.2 years (range, 1-14 yr), 11 (8%) patients developed SLE, 6 (5%) developed lupus-like disease, and 1 (1%) developed myasthenia gravis. The remaining 110 patients (86%) continued to have primary APS. After the univariate analysis, a family history of lupus, the presence of Raynaud phenomenon, migraine, psychiatric features, multiple sclerosis-like features, hemolytic anemia, low C3 and C4, and Coombs positivity conferred a statistically significant risk for the subsequent development of SLE (p < 0.05). Only the presence of Coombs positivity had statistical significance (odds ratio, 66.4; 95% confidence interval, 1.6-2714; p = 0.027) after the logistic regression evaluation. The current study confirms that progression from primary APS to SLE or lupus-like disease is unusual, even after a long follow-up. Only 3 patients developed anti-dsDNA antibodies. The presence of a positive Coombs test might be a marker for the development of SLE in patients with primary APS.

The antiphospholipid (Hughes) syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity in the presence of anticardiolipin antibodies and/or lupus anticoagulant. APS can occur either as a primary disorder or secondary to a connective tissue disease, most frequently systemic lupus erythematosus. Central nervous system (CNS) involvement is one of the most prominent clinical manifestations of APS, and includes arterial and venous thrombotic events, psychiatric features and a variety of other non-thrombotic neurological syndromes. In this review we focus on the common and some of the less common CNS manifestations that have been reported in association with antiphospholipid antibodies.

Patients with Hughes (antiphospholipid) syndrome who develop an initial thrombosis have an increased risk of subsequent thrombotic events. Current therapy to prevent recurrent thrombosis is controversial. While it seems clear that anticoagulant treatment is a better option than anti-aggregants alone, there is no consensus regarding the duration and intensity of oral anticoagulation. The risk of bleeding, the main complication of anticoagulant treatment, and the need for frequent monitoring of the International Normalized Ratio to measure the anticoagulant effect of warfarin concern patients and physicians. In addition, there is some debate about the validity of the International Normalized Ratio in patients with lupus anticoagulant activity. The development of new therapies that target more specific pathogenic mechanisms is highly warranted.

Background. Mycophenolate mofetil (MMF) is an immunosuppressive drug widely used in solid organ transplantation, and it may play an increasing role in autoimmune disease. MMF has been introduced as a novel immunosuppressive agent in systemic lupus erythematosus (SLE), often in patients intolerant of or resistant to conventional immunosuppressive regimens. Methods. We studied 21 patients with SLE, most of whom had previously received courses of cyclophosphamide therapy and had also received courses of azathioprine or methotrexate. Indications for treatment included uncontrolled disease activity and worsening renal involvement. Results. MMF treatment resulted in reduced disease activity, as assessed by the SLEDAI (SLE disease activity index) (P= 0.0001) and decreased proteinuria (P= 0.027) while allowing a significant reduction in oral corticosteroid dose (P= 0.0001). Levels of complement factors C3 and C4 and anti-double-stranded DNA antibodies were not significantly affected. Conclusion. MMF appears to be a safe and effective alternative immunosuppressant for extra-renal and renal disease in SLE not responding to conventional immunosuppressive treatment.

Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non-warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients.

Hughes (antiphospholipid) syndrome (APS) is a noninflammatory autoimmune disease. The most critical pathologic process is thrombosis, which results in most of the clinical features suffered by these patients. Recurrent thrombosis together with an adverse pregnancy history and the presence of antiphospholipid antibodies (aPL) defines the syndrome. Arterial and venous thrombosis can be present in APS, distinguishing this from other prothrombotic states such as protein C, S, or antithrombin III deficiency, where only venous thrombosis occurs. Any organ and any size of vessel (small, medium, or large) can be affected in this disorder; thus, the range of clinical features is extremely wide. In this review, we try to focus on the common and some of the less common clinical manifestations.

OBJECTIVE To determine whether immunoglobulins with affinity for the vascular endothelium displayed any distinguishing behavior during normal and systemic lupus erythematosus (SLE) pregnancy. We also attempted to verify whether isotype expression of anti-endothelial cell antibodies (AECA) would have any predictive value for pregnancy outcome. METHODS Sera from 38 pregnant patients with SLE, 68 normal pregnant women, and 84 nonpregnant healthy controls were studied. IgM- and IgG-AECA were determined by cellular enzyme-linked immunosorbent assay using fixed cultured human umbilical vein endothelial cells. RESULTS A significantly higher level of IgM-AECA was found during normal pregnancy compared with that in healthy nonpregnant controls (mean +/- SD 39 +/- 12% versus 21 +/- 12%; P < 0.0001). Most pregnant patients with SLE did not have increased titers of IgM-AECA, but instead had levels similar to those found in healthy nonpregnant controls (23 +/- 12%; P not significant). The lowest levels of IgM-AECA in lupus pregnancy were associated with preeclampsia (odds ratio 16, P < 0.005). Conversely, IgG-AECA levels were significantly higher in the serum of normal pregnant women and pregnant SLE patients than in the serum of healthy nonpregnant controls (24 +/- 7% and 24 +/- 14% versus 9 +/- 7%; P < 0.0001). CONCLUSION Our results indicate that an active immune response occurs during pregnancy. This response involves increased activity of AECA, suggesting a role of autoantibodies as a possible contributing factor toward fetal tolerance. Our observations further indicate that impaired immune regulation, such as diminished levels of serum IgM-AECA detected in SLE patients, might contribute to the impaired reproductive function commonly found in SLE.

Despite the enormous amount of work focused on the pathogenesis and clinical manifestations of the Hughes or anti-phospholipid syndrome (APS), there is little published on management. Usually, the diagnosis of APS is made after the first thrombotic event, when a thrombophilia screen is performed. These patients have a high risk of recurrent thromboses and current therapy centres on the use of thromboprophylaxis with warfarin. However, a number of clinical questions keep recurring: do arterial and venous thrombosis require the same intensity of anti-coagulation? When should warfarin be stopped? Should patients who develop thrombosis when other risk factors (oral contraceptive pill, prolonged resting etc.) are present be treated like those without any risk factors but the presence of anti-phospholipid antibodies (aPL)? How to manage a patient with recurrent thrombosis despite a high intensity anti-coagulation (International normalized ratio (INR) between 3.0-4.0)? Since many of the patients with aPL are fertile women, a substantial group of patients are diagnosed after recurrent pregnancy loss. Low-dose aspirin for those patients without previous thrombosis and aspirin plus heparin for patients with a history of thrombotic events are the current therapeutic options. However, some questions remain unanswered: does the addition of heparin to low-dose aspirin in women with first trimester recurrent miscarriage but without previous thrombosis improve foetal outcome over and above aspirin alone? Which is the best therapeutic regime during pregnancy for patients with aPL-associated stroke? When should high-dose intravenous gammaglobulin be considered? Finally, very little is known about the risk of thrombosis in individuals positive for aPL but still free of thrombosis. Should these individuals receive any treatment? If so, which one? In this review we attempt to address some of these questions taking into account available data from retrospective and prospective studies and our own clinical experience.

The patent and regulatory data protection periods for the first and second waves of biological agents based on recombinant proteins have started to expire, leaving open the potential for development and regulatory approval of 1 or more “similar” versions of these biologic therapies, termed biosimilars in Europe (BS)—the term that will be used in this chapter—subsequent entry biologics in Canada, or follow-on-biologics in the USA. The development of BS therapies could lead to a substantial saving for patients/health systems and, therefore, increased availability of effective treatments. BSs are similar but not identical to their reference products, because their chemical characteristics are directly related to the manufacturing process, which cannot be precisely duplicated. An exact replica of a protein molecule is extremely difficult if not impossible. Thus, major concerns about short- and long-term safety and efficacy have been raised and should be addressed in the approval process by regulatory agencies. For these reason, BSs require an approach to grant the marketing authorization, different from generics.

The antiphospholipid-antibody syndrome is a thrombophilic disorder in which venous or arterial thrombosis, or both, may occur in patients with antiphospholipid antibodies. The optimal treatment of these patients is unclear. We assessed the efficacy of warfarin, low-dose aspirin, or both in the secondary prevention of thrombosis in patients with the syndrome.One hundred forty-seven patients (124 [84 percent] of whom were female) with the antiphospholipid-antibody syndrome and a history of thrombosis were studied retrospectively. The syndrome was primary in 62 patients and was associated with systemic lupus erythematosus in 66 patients and lupus-like disease in 19. Each patient's history was reviewed.One hundred one patients (69 percent) had a total of 186 recurrences of thrombosis. The median time between the initial thrombosis and the first recurrence was 12 months (range, 0.5 to 144 months). Treatment with high-intensity warfarin (producing an international normalized ratio ofor = 3) with or without low-dose aspirin (75 mg per day) was significantly more effective (P0.001 by the log-rank test) than treatment with low-intensity warfarin (producing an international normalized ratio of3) with or without low-dose aspirin or treatment with aspirin alone in preventing further thrombotic events (recurrence rates per patient-year, 0.013, 0.23, and 0.18, respectively). The rate of recurrence of thrombosis was highest (1.30 per patient-year) during the first six months after the cessation of warfarin therapy. Complications involving bleeding occurred in 29 patients during warfarin therapy and were severe in 7 (0.071 and 0.017 occurrence per patient-year, respectively).The risk of recurrent thrombosis in patients with the antiphospholipid-antibody syndrome is high. Long-term anticoagulation therapy in which the international normalized ratio is maintained at or above 3 is advisable in these patients.

The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q10 (CoQ10). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ10 preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ10 significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS–induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ10.

Antiphospholipid syndrome (APS) is characterized by the development of arterial and/or venous thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL) anticardiolipin (aCL), anti-β2-glycoprotein I (anti-β2GPI), and lupus anticoagulant (LA). Catastrophic antiphospholipid syndrome (CAPS) is a very severe variant of the classic APS, with predominant and extensive small-vessels occlusion that causes multiple organs thrombosis. Multiple thrombotic events occur in a short period of time and frequently lead to a life-threatening condition because of multiorgan failure. The mortality rate is high, but an early diagnosis and treatment with anticoagulation, corticosteroids, plasma exchange, and intravenous immunoglobulin (IVIG) may reduce this rate.

ObjectiveNumerous mechanisms have been proposed to explain the thrombotic/proinflammatory tendency of antiphospholipid syndrome (APS) patients. Prothrombotic monocyte activation by antiphospholipid antibodies involves numerous proteins and intracellular pathways. The anti-inflammatory, anticoagulant and immunoregulatory effects of statins have been aimed as a therapeutic tool in APS patients. This study delineates the global effects of fluvastatin on the prothrombotic tendency of monocytes from APS patients.MethodsForty-two APS patients with thrombosis and 35 healthy donors were included in the study. APS patients received 20 mg/day fluvastatin for 1 month. Blood samples were obtained before the start, at the end and 2 months after the end of treatment.ResultsAfter 1 month of treatment, monocytes showed a significant inhibition of tissue factor, protein activator receptors 1 and 2, vascular endothelial growth factor and Flt1 expression that was related to the inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B/Rel DNA-binding activity. Proteomic analysis showed proteins involved in thrombotic development (annexin II, RhoA and protein disulphide isomerase) with altered expression after fluvastatin administration. In-vitro studies indicated that the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by fluvastatin might inhibit protein prenylation and MAPK activation.ConclusionThe data from this study support the belief that fluvastatin has multiple profound effects in monocyte activity, which might contribute to thrombosis prevention in APS patients.

Objective To investigate the expression of protease-activated receptors (PARs), their potential regulation by anticardiolipin antibodies (aCL), and their association with the expression of other molecules relevant to thrombosis in monocytes obtained from 62 patients with primary antiphospholipid syndrome (APS). Methods Monocytes were isolated from peripheral blood mononuclear cells by magnetic depletion of nonmonocytes. Expression of tissue factor (TF) and PARs 1–4 genes was measured by quantitative real-time reverse transcription–polymerase chain reaction. Cell surface TF and PARs 1–4 expression was analyzed by flow cytometry. For in vitro studies, purified normal monocytes were incubated with purified APS patient IgG, normal human serum IgG, or lipopolysaccharide, in the presence or absence of specific monoclonal antibodies anti–PAR-1 (ATAP2) or anti–PAR-2 (SAM11) to test the effect of blocking the active site of PAR-1 or PAR-2. Results Analysis of both mRNA and protein for the 4 PARs revealed significantly increased expression of PAR-2 as compared with the control groups. PAR-1 was significantly overexpressed in APS patients with thrombosis and in the control patients with thrombosis but without APS. PAR-3 expression was not significantly altered. PAR-4 expression was absent in all groups analyzed. In addition, we demonstrated a correlation between the levels of PAR-2 and the titers of IgG aCL, as well as parallel behavior of TF and PAR-2 expression. In vitro, IgG from APS patients significantly increased monocyte expression of PAR-1 and PAR-2. Inhibition studies suggested that there was direct cross-talk between TF and PAR-2, such that inhibition of PAR-2 prevented the aCL-induced expression of TF. Conclusion These results provide the first demonstration of increased expression of PARs in monocytes from patients with APS. Thus, PAR antagonists might have therapeutic potential as antithrombotic agents in APS.

Few studies have evaluated the impact of viral infections on the daily management of patients with systemic lupus erythematosus (SLE). We analyzed the etiology and clinical features of acute viral infections arising in patients with SLE and their influence on the diagnosis, prognosis, and treatment of SLE. Cases occurring within the last 5 years were selected from the databases of 3 large teaching hospitals. Acute viral infections were confirmed by the identification of specific antiviral IgM antibodies and subsequent seroconversion with detection of specific IgG antibodies. In autopsy studies, macroscopic findings suggestive of viral infection were confirmed by direct identification of the virus or viruses in tissue samples. We performed a MEDLINE search for additional cases reported between January 1985 and March 2008. We included 88 cases (23 from our clinics and 65 from the literature review) of acute viral infections in patients with SLE. Twenty-five patients were diagnosed with new-onset SLE (fulfillment of the 1997 SLE criteria) associated with infection by human parvovirus B19 (n = 15), cytomegalovirus (CMV; n = 6), Epstein-Barr virus (EBV; n = 3), and hepatitis A virus (n = 1). The remaining 63 cases of acute viral infections arose in patients already diagnosed with SLE: in 18 patients, symptoms related to infection mimicked a lupus flare, 36 patients, including 1 patient from the former group who presented with both conditions, presented organ-specific viral infections (mainly pneumonitis, colitis, retinitis, and hepatitis), and 10 patients presented a severe, multiorgan process similar to that described in catastrophic antiphospholipid syndrome-the final diagnosis was hemophagocytic syndrome in 5 cases and disseminated viral infection in 5. Twelve patients died due to infection caused by CMV (n = 5), herpes simplex virus (n = 4), EBV (n = 2), and varicella zoster virus (n = 1). Autopsies were performed in 9 patients and disclosed disseminated herpetic infection in 6 patients (caused by herpes simplex in 4 cases, varicella in 1, and CMV in 1) and hemophagocytic syndrome in 3. A higher frequency of renal failure (54% vs. 19%, p = 0.024), antiphospholipid syndrome (33% vs. 6%, p = 0.023), treatment with cyclophosphamide (82% vs. 37%, p = 0.008), and multisystemic involvement at presentation (58% vs. 8%, p < 0.001); and a lower frequency of antiviral therapy (18% vs. 76%, p < 0.001) were found in patients who died, compared with survivors. The most common viral infections in patients with SLE are parvovirus B19 (predominantly mimicking SLE presentation) and CMV (predominantly presenting in severely immunosuppressed patients). CMV infection may mimic a lupus flare or present with specific organ involvement such as gastrointestinal bleeding or pulmonary infiltrates. Other herpesviruses are common in immunosuppressed SLE patients and may produce a wide range of manifestations. Physicians should examine the pharynx, eyes, skin, and genitalia and should conduct serologic and molecular studies to improve early detection of viral infection in patients with SLE.

Objective Antiphospholipid antibodies (aPL) are closely related to the development of thrombosis, but the exact mechanism(s) leading to thrombotic events remains unknown. In this study, using proteomic techniques, we evaluated changes in protein expression of monocytes from patients with antiphospholipid syndrome (APS) related to the pathophysiology of the syndrome. Methods Fifty-one APS patients were included. They were divided into 2 groups: patients with previous thrombosis, and patients with recurrent spontaneous abortion. As controls, we studied patients with thrombosis but without aPL, and age- and sex-matched healthy subjects. Results The proteins that were more significantly altered among monocytes from APS patients with thrombosis (annexin I, annexin II, protein disulfide isomerase, Nedd8, RhoA proteins, and Hsp60) were functionally related to the induction of a procoagulant state as well as to autoimmune-related responses. Proteins reported to be connected to recurrent spontaneous abortion (e.g., fibrinogen and hemoglobin) were also determined to be significantly deregulated in APS patients without thrombosis. In vitro treatment with IgG fractions purified from the plasma of APS patients with thrombosis changed the pattern of protein expression of normal monocytes in the same way that was observed in vivo for monocytes from APS patients with thrombosis. Conclusion For the first time, proteomic analysis has identified novel proteins that may be involved in the pathogenic mechanisms of APS, thus providing potential new targets for pathogenesis-based therapies for the disease.

The importance of cerebral disease in patients with the Hughes syndrome is now becoming more widely recognized. The range of neuropsychiatric manifestations of APS is comprehensive, and includes focal symptoms attributable to lesions in a specific area of the brain as well as diffuse or global dysfunction. Patients with APS frequently present with strokes and TIA, but a wide spectrum of other neurologic features-also including non thrombotic neurologic syndromes-has been described in association with the presence of aPL. The recognition of APS has had a profound impact on the understanding and management of the treatment of CNS manifestations associated with connective tissue diseases, in particular, SLE. Many patients with focal neurologic manifestations and aPL, who a few years ago would have received high-dose corticosteroids or immunosuppression, are often successfully treated with anticoagulation. In our opinion, testing for aPL may have a major diagnostic and therapeutic impact not only in patients with autoimmune diseases and neuropsychiatric manifestations, but also in young individuals who develop cerebral ischemia, in those with atypical multiple sclerosis, transverse myelitis, and atypical seizures. We would also recommend testing for aPL for young individuals found with multiple hyperintensity lesions on brain MRI in the absence of other possible causes,especially when under the age of 40 years. It is our practice to anticoagulate patients with aPL suffering from cerebral ischemia with a target INR of 3.0 to prevent recurrences. Low-dose aspirin alone (with occasional exceptions)does not seem helpful to prevent recurrent thrombosis in these patients. Our recommendation, once the patient has had a proven thrombosis associated with aPL, is long-term (possibly life-long) warfarin therapy. Oral anti coagulation carries a risk of hemorrhage, but in our experience the risk of serious bleeding in patients with APS and previous thrombosis treated with oral anticoagulation to a target INR of 3.5 was similar to that in groups of patients treated with lower target ratios. Although a double-blind crossover trial comparing low molecular weight heparin with placebo in patients with aPL and chronic headaches did not show a significant difference in the beneficial effect of low molecular weight heparin versus placebo, in our experience selected patients with aPL and neuropsychiatric manifestations such as seizures, severe cognitive dys-function, and intractable headaches unresponsive to conventional treatment may respond to anticoagulant treatment. The neurologic ramifications of Hughes syndrome are extensive, and it behoves clinicians in all specialties to be aware of this syndrome because treatment with anticoagulation may profoundly change the outlook for these patients.

Increased TF expression may contribute to thrombosis in patients with APS. This effect might ultimately depend on antibody engagement of PL binding proteins on the monocyte and the EC surface, leading to signal transduction and altered cell activity. Understanding the intracellular mechanism(s) of aPL mediated TF activation may help to establish new therapeutic approaches to revert the prothrombotic state observed in APS patients.

The antiphospholipid syndrome (APS) is characterized by thrombosis or pregnancy morbidity in the presence of antiphospholipid autoantibodies (aPL). aPL are a heterogeneous family of autoantibodies with diverse cross-reactivities whose origin and role have not been fully elucidated. Many of the autoantibodies associated with APS are directed against phospholipid-binding plasma proteins, such as β2-GPI and prothrombin, or phospholipid-protein complexes. The mechanisms by which aPL cause thrombosis are not completely understood. There is no unique mechanism able to explain all symptoms associated with the presence of aPL. Different theories have been proposed, including the effect of aPL on endothelial cells, monocytes, and platelets. aPL are able to recognize, injure, or activate cultured vascular endothelial cells. Cultured endothelial cells incubated with aPL express increased levels of cell adhesion molecules and tissue factor (TF), an effect mediated by β2-GPI, and may promote inflammation and thrombosis. Overexpression of TF has been also shown in monocytes in vitro and ex vivo. TF is the major initiator of coagulation in vivo; thus, its dysregulation may be one of the most important contributors to thrombosis. Effects of aPL upon platelets are not completely elucidated. aPL bind anionic phospholipid but they are normally in the inner side of cell membranes. When platelets are activated by different agonists, anionic phospholipids are exposed. There is some evidence showing that activated platelets are present in aPL-positive patients. Increased levels of β-thrombomodulin, and microvesicle formation seem to support this hypothesis. Activated platelets may contribute to thrombosis by persistent exposure of a procoagulant surface.

OBJECTIVE—To determine the prevalence of thrombocytopenia in a group of patients suffering from the antiphospholipid syndrome (APS) and to investigate whether these patients may have any particular clinical or serological features. METHODS—Retrospective analysis. A group of 171 APS patients seen in our department were studied for the presence of thrombocytopenia. Clinical and serological features of these patients were analysed by standard methods and each of them was correlated to the presence of thrombocytopenia and compared with those found in the group without thrombocytopenia. RESULTS—Each of the patients studied had a minimum of three platelet counts during the follow up period. Forty (23.4%) were found to have thrombocytopenia; 13 with persistently low and 27 patients with intermittently low platelet counts. There were no statistically significant differences in sex, age, disease duration or diagnosis when compared with the group of APS patients without thrombocytopenia. Thrombocytopenia was associated with thrombosis in 18, with miscarriages in five, and with both of these features in 13 patients. It was the only manifestation of the APS in four patients. All patients had persistently positive tests for antiphospholipid antibodies concomitantly with the low platelet counts. No significant association was found between the presence of thrombocytopenia and clinical or serological manifestations in APS patients. CONCLUSION—This study showed a prevalence of thrombocytopenia of 23.4% in APS. These patients did not present any significant clinical or serological features that distinguish them from those patients without thrombocytopenia.

Objective Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL). In patients with primary APS, expression of tissue factor (TF) on the surface of monocytes is increased, which may contribute to thrombosis in these patients. However, the intracellular mechanisms involved in aPL-mediated up-regulation of TF on monocytic cells are not understood. This study was undertaken to investigate the intracellular signals induced by aPL that mediate TF activation in monocytes from APS patients. Methods We analyzed, both in vivo and in vitro, aPL interactions with proteins that have signaling functions, including mitogen-activated protein kinases (MAP kinases) and NF-κB/Rel proteins. Results In vivo studies demonstrated significantly higher levels of both TF messenger RNA and TF protein in monocytes from APS patients compared with controls. At the molecular level, increased proteolysis of IκBα and activation of NF-κB were observed. Constitutive activation of both p38 and ERK-1 MAP kinases was also found. Treatment of normal monocytes with aPL activated ERK-1 and p38 MAP kinases, as well as the IκB/NF-κB pathway, in a dose-dependent manner. NF-κB activation and IκBα degradation induced by aPL were inhibited by the NF-κB inhibitor SN50 and the p38 MAP kinase inhibitor SB203580, thus suggesting crosstalk between these pathways. However, the MEK-1/ERK inhibitor PD98059 did not affect aPL-induced NF-κB binding activity. TF expression induced by aPL was significantly inhibited by combined treatment with the 3 inhibitors. Conclusion Our results suggest that aPL induces TF expression in monocytes from APS patients by activating, simultaneously and independently, the phosphorylation of MEK-1/ERK proteins, and the p38 MAP kinase–dependent nuclear translocation and activation of NF-κB/Rel proteins.

practice in the mid-1950s; since that time, it has had a remarkable checkered history. It was used early on as an over-the-counter sedative (Mellin and Katzenstein 1962), and then in the treatment of morning sickness in pregnancy. However, in 1961, thalidomide was withdrawn from the market because of the discovery of its potential teratogenicity– it was associated with up to 12,000 cases of birth defects, particularly phocomelias (Mellin 1962, Randall 1990). Four years later, Sheskin serendipitously discovered that thalidomide had marked clinical efficacy in erythema nodosum leprosum (Sheskin 1965). Subsequently, a variety of conditions, including infectious, autoimmune, inflammatory, and malignant, have been shown to respond to thalidomide. Examples of these conditions include human immunodeficiency virus (HIV) infection (Reyes-Teran et al. 1996), rheumatoid arthritis (Gutierrez-Rodriguez et al. 1989), Behcet’s syndrome (Hamuryudan et al. 1998), graft-versus-host disease (Vogelsang et al. 1993), multiple myeloma (Singhal et al. 1999), and cutaneous features of lupus erythematosus (LE) (Knop et al. 1983). The latter include systemic LE (SLE) with cutaneous features, discoid LE (DLE), and subacute cutaneous LE (SCLE). The common denominator of the previously mentioned differing conditions seems to be that they are all characterized by inflammation, immune dysregulation, or both. Thalidomide has been shown to have immunomodulatory, immunosuppressive, and anti-inflammatory actions, which may explain its therapeutic efficacy. Furthermore, thalidomide is often effective in conditions in which standard therapies have failed to make an impression, for example, severe ulceration in Behcet’s syndrome or severe cutaneous lupus. Clinical use of thalidomide must, of course, be tightly regulated and supervised, not only because of the potential for teratogenicity, especially as many patients with lupus are young women, but also for the development of peripheral neuropathy.In this article,we discuss possible mechanisms of action and the clinical experience of thalidomide in the treatment of cutaneous features of LE.

Purpose Thalidomide is effective for the treatment of severe cutaneous lupus. Our aim was to study the safety and efficacy of different doses of thalidomide in this condition. Methods We studied patients with severe cutaneous lupus that was unresponsive to antimalarials, prednisolone, methotrexate, azathioprine, and cyclosporin A. Starting doses of 100 mg daily (n = 16 patients), 50 mg daily (n = 17), or 50 mg on alternate days (n = 15) were compared. The response to thalidomide was categorized as complete remission, partial remission, or no visible improvement. All patients received a baseline electromyogram (EMG) followed by repeat EMG every 3 to 6 months, or sooner if neuropathic symptoms developed. Results Forty-eight patients (46 female; mean [± SD] age, 44 ± 12 years; range, 22 to 71 years) with discoid lupus (n = 18), subacute cutaneous lupus (n = 6), or systemic lupus erythematosus with skin involvement (n = 24) were included. The response rate was 81%, including 29 patients (60%) in complete remission and 10 (21%) in partial remission. Nine patients (19%) failed to respond. Thirteen patients (27%) developed peripheral neuropathy, which was EMG-proven in 11, including 4 patients in the 50-mg alternate-day group. Other side effects included drowsiness, constipation or abdominal pain, and amenorrhea. The relapse rate after stopping thalidomide was 67% (26/39). There was no association between a positive response to the drug and either starting doses or cumulative dose. Similarly, no association was found between peripheral neuropathy and the starting or cumulative dose. Conclusion Thalidomide is effective for the treatment of severe cutaneous lupus. There were no clear dose-dependent effects. However, the high incidence of neurotoxicity, even at low doses, suggests that it may be most useful as a remission-inducing drug.

Background: Lupus nephritis (LN) is a common manifestation in patients with systemic lupus erythematosus (SLE). Autoantibodies and ethnicity have been associated with LN, but the results are controversial. Objective: To study the immunological and demographic factors associated with the development of LN. Patients and methods: A retrospective case-control study of 127 patients with biopsy-proven LN, and 206 randomly selected patients with SLE without nephritis as controls was designed. All patients had attended our lupus unit during the past 12 years. Standard methods were used for laboratory testing. Results: Patients with LN were significantly younger than the controls at the time of SLE diagnosis (mean (SD) 25.6 (8.8) years v 33.7 (12.5) years; p

SLE has a high prevalence in Afro-Caribbean populations but has been reported to be rare in west Africa. We assessed prevalence (per 100000) of SLE in women in an area of south London and estimated it to be 177 (95% CI 135-220) in Afro-Caribbeans, 110 (58-163) in west Africans, and 35 (26-43) in Europeans. The high prevalence of SLE in recent migrants from west Africa suggests that the disease is not rare in west Africa, and that there is a genetic basis for the high risk of SLE in people of west African descent compared with other groups.

Hughes (antiphospholipid) syndrome (APS) can mimic multiple sclerosis (MS). We analyzed the clinical, laboratory, and imaging findings of MS-like expression in a cohort of patients with APS in an attempt to identify parameters that might differentiate the 2 entities. We studied 27 patients who were referred to our unit with the diagnosis of probable or definite MS made by a neurologist. All patients were referred to our lupus clinic because of symptoms suggesting an underlying connective tissue disease, uncommon findings for MS on magnetic resonance imaging (MRI), atypical evolution of MS, or antiphospholipid antibody (aPL) positivity. aPL, antinuclear antibody (ANA), anti-dsDNA, and anti-extractable nuclear antigen (ENA) antibodies were measured by standard methods. MRI was performed in every patient and compared with MRI of 25 definite MS patients who did not have aPL. An index severity score was calculated based on the size and number of increased signal intensity areas in MRI. In the past medical history, 8 patients with primary APS and 6 with APS secondary to systemic lupus erythematosus (SLE) had had symptoms related to these conditions. Neurologic symptoms and physical examination of the patients were not different from those common in MS patients. Laboratory findings were not a useful tool to distinguish APS from MS. When MRI from APS patients was compared globally with MRI from MS patients, MS patients had significantly increased severity score in white matter (p < 0.001), cerebellum (p = 0.035), pons (p < 0.015), and when all areas were taken together (p < 0.001). Patients with APS had significantly increased scores in the putamen (p < 0.01). No differences were noticed in the degree of atrophy. When taken individually, MRI from APS patients could not be distinguished from MRI from MS patients. Most of the patients with primary APS showed a good response to oral anticoagulant treatment. In patients with secondary APS, the outcome was poorer. Hughes syndrome (APS) and MS can be difficult to distinguish. A careful medical history, a previous history of thrombosis and/or fetal loss, an abnormal localization of the lesions in MRI, and the response to anticoagulant therapy might be helpful in the differential diagnosis. We believe that testing for aPL should become routine in all patients with MS.

Objective The antiphospholipid syndrome (APS) is a disorder of recurrent thrombosis, pregnancy loss, and thrombocytopenia associated with the production of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). The mechanisms of thrombus formation remain unknown. Tissue factor (TF), an inducible cell glycoprotein, is a major initiator of coagulation in vivo. The present study was therefore undertaken to investigate TF expression and procoagulant activity on monocytes from patients with primary APS and its correlation with thrombotic events. Methods Three groups of patients were studied: group 1 comprised 23 primary APS patients with thrombosis, group 2 consisted of 10 primary APS patients without thrombosis, and group 3 contained 20 patients with thrombosis but without antiphospholipid antibodies. Twenty age- and sex-matched healthy blood donors were used as controls (group 4). Anticardiolipin antibodies were measured by enzyme-linked immunosorbent assay (ELISA) and LAC by standard methodology. Cell surface expression of TF on monocytes was assessed by flow cytometry. The amount of TF in cell lysates (TF(Ag)) and soluble TF(Ag) plasma levels were analyzed by ELISA, and the TF-related procoagulant activity (PCA-TF) on intact cells and cell lysates by a chromogenic assay. Levels of the cytokines that influence TF production, i.e., tumor necrosis factor alpha (TNF alpha) and interleukin-1beta (IL-1beta), were determined by ELISA. Results Cell surface expression of TF was increased in group 1 (mean +/- SEM 50.2 +/- 4% positive cells) compared with group 2 (14.6 +/- 1.6%), group 3 (16.8 +/- 3.7%), and group 4 (14.1 +/- 1.6%). TF(Ag) levels were also elevated in group 1 (215.8 +/- 11.2 pg/10(6)) compared with group 2 (150.8 +/- 15.2), group 3 (101.4 +/- 14.8), and group 4 (80.32 +/- 5.5). PCA-TF on intact cells and cell lysates was significantly increased in group 1 (148.8 +/- 16.3 units/10(5) lysate cells, compared with 54.5 +/- 11.5, 38.6 +/- 9.7, and 22.5 +/- 3.1 in groups 2, 3, and 4, respectively). Among group 1 patients, there was a significant increase in the degree of TF expression in those positive for IgG aCL, but not in those positive for IgM aCL or LAC. TNF alpha and IL-1beta plasma levels did not differ significantly between any of the groups. Conclusion These results suggest that monocyte TF expression is directly involved in the pathogenesis of thrombotic complications in patients with the primary APS.

Background Prolonged anticoagulation is the treatment of choice for patients with thrombosis and the antiphospholipid syndrome. However, there is still debate about the optimum intensity of anticoagulation. Methods The study included 66 patients with antiphospholipid syndrome (Sapporo criteria) and previous thrombosis. All were receiving oral anticoagulation to a target international normalized ratio of 3.5. Every patient was individually interviewed to recall major bleeding and thrombotic episodes during the previous 12 months. Results Patients were mainly women and white. The rate of major bleeding was 6 cases per 100 patient-years (95% confidence interval [CI] 1.6-15.0). The rate of intracranial bleed was 1.5 per 100 patient-years (95% CI, 0.04-8.4). None of the bleeding episodes was fatal. The rate of thrombotic recurrences was 9.1 cases per 100 patient-years (95% CI, 3.3-19.6). Most recurrences took place in the same vascular bed as the original thrombosis. Age, time receiving anticoagulant therapy, primary vs secondary antiphospholipid syndrome, positivity for anticardiolipin antibodies, positivity for lupus anticoagulant, previous arterial thrombosis, previous stroke, previous venous thrombosis, and previous thrombocytopenia were not predictive of bleeding events. However, the risk of thrombotic recurrences was independently higher in patients who were receiving anticoagulation for longer periods. Conclusions The risk of intracranial and fatal bleeding in patients with definite antiphospholipid syndrome and previous thrombosis treated with oral anticoagulation to a target international normalized ratio of 3.5 is similar than in groups of patients treated to lower target ratios. The risk of thrombotic recurrences, even during anticoagulation, was high. Most recurrences took place in the same territory as original thromboses.

SummaryAntiphospholipid antibodies (aPL) may stimulate tissue factor (TF) expression in cultured endothelial cells and monocytes, but there are discrepancies as to the expression of TF in the patients with antiphospholipid syndrome (APS). By using reverse transcription and polymerase chain reaction amplification, we have analysed TF mRNA accumulation in freshly isolated mononuclear blood cells (MBC) of 14 patients with primary APS (PAPS) and six normal controls. TF mRNA accumulation was low or absent in uncultured MBC from all normal controls, but was elevated in uncultured MBC from nine of the patients as well as in normal MBC incubated with 100 ng/ml lipopolysaccharide (LPS). Mean levels of TF mRNA, as measured by densitometry, were higher in MBC from patients (N = 14) than in those from controls (N = 6, P = 0.009), and in MBC from patients with a history of thrombosis (N = 9) than in those from patients without thrombosis (N = 5, P = 0.02). Uncultured MBC of patients with thrombosis accumulated TF mRNA at similar levels to LPS-treated normal MBC. Increased levels of TF mRNA were found in eight of ten patients with conventional aPL (ie, anti-cardiolipin antibodies [aCL] and/or lupus anticoagulant [LA]) and littleif any accumulation of TF mRNA was observed in three of four patients without aPL at the time of study. These data strongly suggest that circulating monocytes of many patients with PAPS are subjected to an up-regulated TF expression that may well explain their prothrombotic state. Although the presence or absence of TF mRNA in MBC was associated with, respectively, the presence or absence of conventional aPL in 11 of the 14 patients studied, our study cannot exclude the involvement of factors other than aCL or LA in inducing TF expression.