The global antiphospholipid syndrome score in women with systemic lupus erythematosus and adverse pregnancy outcomes.

OBJECTIVES: To validate the global antiphospholipid syndrome score (GAPSS) in a cohort of women with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL). METHODS: This retrospective study included 143 women ever pregnant with SLE who presented in our outpatient clinic were included. Data on cardiovascular risk factors and aPL status were retrospectively collected and their individual GAPSS score was calculated. RESULTS: Significantly higher GAPSS values were found in women with any placental medicated complication (such as foetal death, placental abruption, prematurity, pre-eclampsia or intrauterine growth restriction (IUGR)) (GAPSS 8.2±3.0 vs. 3.5±3.0, p<0.001). Significantly higher GAPSS values were also found in those with recurrent miscarriages (RM) <10 weeks, foetal death, placental abruption, prematurity, pre-eclampsia or IUGR) (GAPSS 8.3±4.5 vs. 3.2±2.6, p<0.001). Patients with 3 or more consecutive early miscarriages (<10 weeks), foetal death, miscarriage <10 weeks' gestation, premature birth (<34 weeks), pre-eclampsia (<34 weeks), stillbirth, and placental infarction had significantly higher GAPSS values compared to those without previous pregnancy complications. The odds ratio of having any pregnancy morbidity when having a GAPSS value ≥8 was 20 compared to those with a GAPSS of ≤1 (p<0.001). CONCLUSIONS: Women with a history of aPL-related pregnancy complications had higher GAPSS values in this retrospective cohort compared to women without pregnancy complications. This study is the first step to assess the clinical utility of the GAPSS score in pregnancy. A prospective validation is needed.

16th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends.

Antiphospholipid syndrome (APS), an acquired autoimmune thrombophilia, is characterised by thrombosis and/or pregnancy morbidity in association with persistent antiphospholipid antibodies. The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends reviewed the current status with regard to existing and novel treatment trends for APS, which is the focus of this Task Force report. The report addresses current treatments and developments since the last report, on the use of direct oral anticoagulants in patients with APS, antiplatelet agents, adjunctive therapies (hydroxychloroquine, statins and vitamin D), targeted treatment including rituximab, belimumab, and anti-TNF agents, complement inhibition and drugs based on peptides of beta-2-glycoprotein I. In addition, the report summarises potential new players, including coenzyme Q10, adenosine receptor agonists and adenosine potentiation. In each case, the report provides recommendations for clinicians, based on the current state of the art, and suggests a clinical research agenda. The initiation and development of appropriate clinical studies requires a focus on devising suitable outcome measures, including a disease activity index, an optimal damage index, and a specific quality of life index.

Thrombotic risk assessment in antiphospholipid syndrome: the role of new antibody specificities and thrombin generation assay.

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by the presence of antiphospholipid antibodies (aPL) in subjects presenting with thrombosis and/or pregnancy loss. The currently used classification criteria were updated in the international consensus held in Sidney in 2005. Vascular events seem to result of local procoagulative alterations upon triggers influence (the so called "second-hit theory"), while placental thrombosis and complement activation seem to lead to pregnancy morbidity. The laboratory tests suggested by the current classification criteria include lupus anticoagulant, a functional coagulation assay, and anticardiolipin and anti-ß2-glycoprotein-I antibodies, generally detected by solid phase enzyme-linked immunosorbent assay. The real challenge for treating physicians is understanding what is the actual weight of aPL in provoking clinical manifestations in each case. As thrombosis has a multi-factorial cause, each patient needs a risk-stratified approach. In this review we discuss the role of thrombotic risk assessment in primary and secondary prevention of venous and arterial thromboembolic disease in patients with APS, focusing on new antibody specificities, available risk scoring models and new coagulation assays.

Low-dose aspirin vs low-dose aspirin plus low-intensity warfarin in thromboprophylaxis: a prospective, multicentre, randomized, open, controlled trial in patients positive for antiphospholipid antibodies (ALIWAPAS).

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/.

Can anticoagulation be withdrawn in APS patients after aPL negativization?

Long-term vitamin K antagonist (VKA) anticoagulation is the cornerstone of the management of subjects with thrombotic antiphospholipid syndrome (APS). Recent investigations have opened up new discussion points regarding the potential for stopping anticoagulant medication in patients with a history of thrombotic APS who no longer have detectable aPL (the so called aPL negativization). Despite the lack of unanimous agreement, some experts agreed on defining aPL negativization as the presence of two negative determinations, 1 year apart. What to do in order to optimize the management of these subjects with thrombotic APS when aPL turn negative is still a matter of debate. In this review, we aim to summarize the main evidence highlighting the magnitude of aPL negativizing among patients with APS and the features to keep in mind when considering (or not) stopping anticoagulation.

Steroids in Lupus: Enemies or Allies.

Glucocorticoids are the gold standard treatment for reducing immune activation and inflammation in a wide range of inflammatory and systemic autoimmune diseases. Glucocorticoids have potent and fast actions that quickly relieve some symptoms and lower mortality in some life-threatening conditions, but they also have side effects that limit the duration of treatment and the dose used. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the involvement of numerous organs and systems and the production of autoantibodies. Most current treatments include the use of corticosteroids and immunosuppressive medications. Glucocorticoids in SLE have been classically used not only to induce remission or treat an acute situation but also as maintenance therapy. During the last decades, new approaches to managing SLE have emerged, but corticosteroids continue to be part of all therapeutic regimes. There is more and more evidence about the side effects related to the use (or abuse) of steroids and their relationship with the accrual damage. In this manuscript, we try to make a critical review of the published literature about the benefit and side effects/damage that can be attributed to the use of glucocorticoids.

Clinical-Pathological Characteristics of Renal Injuries Identify Different Clusters in Patients With Antiphospholipid Antibodies.

Introduction: Significant heterogeneity still exists in the nomenclature of renal involvement in antiphospholipid syndrome (APS). Methods: We applied a hierarchical cluster analysis to determine subgroups of patients according to clinical, laboratory, and renal histology characteristics in a cohort of subjects with confirmed antiphospholipid antibodies (aPL) positivity and biopsy proven aPL-related renal injuries. Kidney outcomes were then assessed at 12 months. Results: A total of 123 aPL-positive patients were included in the study (101 [82%] female, 109 [88.6%] with systemic lupus erythematosus [SLE], 14 (11.4%) with primary APS [PAPS]). Three clusters were identified. Twenty-three patients (18.7%) were included in the first cluster (cluster 1), characterized by a higher prevalence of glomerular capillary and arteriolar thrombi and fragmented red blood cells in the subendothelial space. Cluster 2 included 33 patients (26.8%) and showed a higher prevalence of fibromyointimal proliferative lesions as seen in hyperplastic vasculopathy. Cluster 3 was the largest (67 patients, mainly with SLE) and was characterized by higher prevalence of subendothelial edema, of both glomerular capillaries and arterioles. Conclusion: Three different clusters of patients with aPL and renal injuries emerged from our study as follows: the first, with the worst renal prognosis, was associated with features of thrombotic microangiopathy (TMA), thrombosis, triple aPL positivity and higher adjusted Global APS Score (aGAPSS) values; the second, characterized by hyperplastic vasculopathy with an intermediate prognosis, was seen more frequently in patients with cerebrovascular manifestations; and the third, more benign in terms of outcomes and with no overt association with thrombotic features, was characterized by endothelial swelling in concomitant lupus nephritis (LN).

Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study.

The effect of additional treatments combined with conventional therapy on pregnancy outcomes was examined in high-risk primary antiphospholipid syndrome (PAPS) patients to identify the most effective treatment strategy. The study's inclusion criteria were (1) positivity to lupus anticoagulant alone or associated with anticardiolipin and/or anti-ß2 glycoprotein I antibodies; (2) a history of severe maternal-foetal complications (Group I) or a history of one or more pregnancies refractory to conventional therapy leading to unexplained foetal deaths not associated with severe maternal-foetal complications (Group II). Two different additional treatments were considered: oral-low-dose steroids (10-20 mg prednisone daily) and/or 200 to 400 mg daily doses of hydroxychloroquine and parenteral-intravenous immunoglobulins at 2 g/kg per month and/or plasma exchange. The study's primary outcomes were live birth rates and pregnancy complications. A total of 194 pregnant PAPS patients attending 20 tertiary centres were retrospectively enrolled. Hydroxychloroquine was found to be linked to a significantly higher live birth rate with respect to the other oral treatments in the Group II patients. The high (400 mg) versus low (200 mg) doses of hydroxychloroquine (p = 0.036) and its administration before versus during pregnancy (p = 0.021) were associated with a significantly higher live birth rate. Hydroxychloroquine therapy appeared particularly efficacious in the PAPS patients without previous thrombosis. Parenteral treatments were associated with a significantly higher live birth rate with respect to the oral ones (p = 0.037), particularly in the Group I patients. In conclusion, some additional treatments were found to be safe and efficacious in high-risk PAPS pregnant women.

Rate of Adverse Effects of Medium- to High-Dose Glucocorticoid Therapy in Systemic Lupus Erythematosus: A Systematic Review of Randomized Control Trials.

BACKGROUND AND OBJECTIVES: 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 prednisone <7.5 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Emerging therapies in systemic lupus erythematous: from clinical trial to the real life.

Systemic lupus erythematous (SLE) is a chronic autoimmune disease characterised by multisystem involvement and a relapsing remitting course. SLE is a highly heterogeneous condition, with wide variations in both the presentation and severity of disease and the biological markers identified. The use of biologics in SLE has lagged behind that of other rheumatological conditions such as rheumatoid arthritis, in part due to the diverse clinical manifestations of SLE, making it difficult to design appropriate trials for novel treatments. As such, broad immunosuppressive treatment regimens are still widely used in SLE. Nevertheless, in recent years, elucidation of some aspects of SLE pathogenesis have allowed the development of therapies targeted at molecular mediators of SLE. This review provides an update of biological available therapies and those currently under development.

Long-term follow-up in 128 patients with primary antiphospholipid syndrome: do they develop lupus?

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.

Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens.

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.

Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5.

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.

14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends.

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.

Mycophenolate mofetil in systemic lupus erythematosus: efficacy and tolerability in 86 patients.

OBJECTIVE: To assess the indications, efficacy, and tolerability of mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE) resistant to other immunosuppressive therapy. METHODS: Records of 93 patients with SLE were retrospectively reviewed. Seven patients were excluded. The remaining 86 patients received other immunosuppressive drugs before MMF. Efficacy was measured by changes in daily oral prednisolone dose, European Consensus Lupus Activity Measurement Index (ECLAM), erythrocyte sedimentation rate (ESR), C-reactive protein, and dsDNA antibody titer. In renal patients, changes in serum creatinine, creatinine clearance, chromium-51 EDTA glomerular filtration rate (EDTA-GFR), and 24 hour urine protein excretion were also evaluated. RESULTS: Indications for MMF were mainly renal involvement (59% of patients), uncontrolled disease activity (14%), and other SLE related manifestations (13%). Overall, we found a significant reduction in the steroid dosage, ECLAM, ESR, and anti-dsDNA antibody titer. Renal patients (n = 35) showed a significant reduction in urinary 24 hour protein excretion. Levels of serum creatinine, creatinine clearance, and EDTA-GFR showed no significant change during treatment. Thirty-seven patients (42.8%) developed adverse events. Gastrointestinal intolerance in 25 (29%) and infections in 20 (23.2%) were the most frequent. The drug was discontinued in 14 (16.3%) patients due to side effects and 6 patients discontinued MMF because they achieved disease remission and were trying to conceive. MMF was stopped due to lack of efficacy in 12 patients. CONCLUSION: Our data suggest that MMF is a good therapeutic alternative for patients with SLE and renal involvement or refractory disease activity.

Treatment and monitoring of patients with antiphospholipid antibodies and thrombotic history (Hughes syndrome).

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.