A. Ruffatti

Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study

Objectives: To asses risk factors for a first thrombotic event in antiphospholipid antibody (aPL) positive carriers and evaluate the efficacy of prophylactic treatments. Methods: Recruitment criteria were age 18–65 years, no history of thrombosis, positivity for lupus anticoagulant and/or IgG/IgM anticardiolipin antibody (aCL) on ⩾2 occasions at least 6 weeks apart. Demographic, laboratory and clinical parameters were collected at enrolment and at the time of the thrombotic event. Results: 370 patients/subjects (mean (SD) age 34 (9.9) years) were analysed retrospectively for a mean (SD) follow-up of 59.3 (45.5) months. Thirty patients (8.1%) developed a first thrombotic event during follow-up. Hypertension and medium/high levels of IgG aCL were identified by multivariate logistic regression analysis as independent risk factors for thrombosis. Thromboprophylaxis during high-risk and long-term periods was significantly protective. Conclusions: Hypertension or medium/high titres of IgG aCL are risk factors for a first thrombotic event in asymptomatic aPL carriers and primary prophylaxis is protective.

Laboratory and clinical features of pregnant women with antiphospholipid syndrome and neonatal outcome

To evaluate the relationship between the antiphospholipid profile and clinical characteristics of pregnant women with antiphospholipid syndrome (APS) and neonatal outcome.

Antiphospholipid antibodies (aPL) in systemic lupus erythematosus. Are they specific tools for the diagnosis of aPL syndrome

OBJECTIVE--Antiphospholipid antibody (aPL) specificity for aPL-related events was evaluated in systemic lupus erythematosus (SLE). METHODS--A study was carried out on 105 patients affected with SLE comparing the prevalence of lupus anticoagulant (LA) and IgG and IgM anticardiolipin antibodies (aCL) between patients with and without features of antiphospholipid syndrome (APS). Antiphospholipid antibody profile was subsequently evaluated in the aPL positive patients with and without aPL-related events, thus excluding the patients with complications of APS possibly due to factors other than aPL. RESULTS--LA showed a strong association with thrombosis and livedo reticularis, and IgG aCL with thrombosis and neurological disorders, while no clinical features were associated with IgM aCL. A considerable number of aPL positive patients with no aPL-related manifestations was also observed, suggesting the low specificity of aPL assays (54.4%). When studying the 60 aPL positive patients, LA was specific (91.3%) for the diagnosis of aPL-related thrombosis, whereas aCL were not specific, although IgG aCL mean levels were higher in patients with arterial thrombosis than in those without APS features. CONCLUSIONS--LA but not aCL positivity is a specific tool for the diagnosis of thrombotic complications due to aPL in SLE.

Secondary prevention in thrombotic antiphospholipid syndrome.

Secondary prevention of venous thromboembolism in antiphospholipid syndrome (APS) is usually made using vitamin K antagonists (VKAs) to maintain an international normalized ratio (INR) between 2.0 and 3.0. The optimal intensity of anticoagulation was determined in two prospective randomized controlled trials, both excluding the benefit of more intense anticoagulation. The same regimen is also recommended in patients with APS and arterial thromboembolism as aspirin does not appear to protect against recurrences. The duration of treatment is usually indefinite because of a substantial risk of recurrence.

Risk-based secondary prevention of obstetric antiphospholipid syndrome

Treatment of pregnant women with antiphospholipid syndrome (APS) should be set apart from that from thrombotic APS patients. Patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with a prophylactic dose of heparin plus low-dose aspirin; whereas, those with previous vascular thrombosis alone or associated with previous pregnancy morbidity, are commonly treated with a therapeutic dose of heparin generally combined with low-dose aspirin. However, in about 20% of pregnant APS women these regimens fail. In this context, we conducted a case-control study on a large multicentre cohort of conventionally treated pregnancies to verify whether specific laboratory profiles and/or clinical characteristics are predictive of unsuccessful pregnancy outcome during conventional treatments. Multivariate analysis showed that pregnancy failure during conventional therapies was independently associated with a history of both thrombosis and pregnancy morbidity, the presence of systemic lupus erythematosus (SLE) or other systemic autoimmune diseases and triple antiphospholipid antibody positivity. With the aim to discover the most effective and safe treatments in high-risk pregnant APS women a large-scale multicentre study focusing on the effect of treatments on pregnancy outcome in women with APS and further risk factors for pregnancy failure has been designed.

Interpretation of laboratory data and need for reference laboratories

A single positive laboratory test among those exploring the presence of antiphospholipid antibodies is not associated with thromboembolic events and does not identify patients with antiphospholipid syndrome. On the other hand, more than one laboratory test positive, and in particular all three tests positive, is strongly associated to thromboembolic events and identifies high risk patients. Triple positivity is in fact related to the presence of a specific anti-β2-glycoprotein I (anti-Domain I) antibody, also able to prolong coagulation tests. Monoclonal antibodies against Domain I with Lupus Anticoagulant activity might be candidate material for standardization of antiphospholipid assays. Much work remains to be done in this field.

Are biological drugs safe in pregnancy

The introduction of biological therapies has significantly improved the outcome of inflammatory rheumatic diseases. As most of these diseases affect women and men in childbearing age, some concerns have been voiced as to the safety of these drugs in relation to reproduction and pregnancy. Data from many hundreds of pregnancies in patients affected by inflammatory bowel disease and inflammatory arthritis have suggested that exposure to anti-TNF therapies at conception and/or during pregnancy is not associated with adverse pregnancy outcomes or any increase in congenital abnormalities. However, the exposure to anti-TNFα agents, particularly to monoclonal antibodies, in late pregnancy is associated with high drug levels in the newborn and their long-term effects on children remain unknown. Therefore, limiting the use of anti-TNFα to the first 30 weeks of pregnancy is recommended to reduce fetal exposure. Live-virus vaccines should be given only when levels of anti-TNFα drugs are undetectable in the serum of infants. Studies suggest that many of these drugs do enter breast milk in small amounts, but the extent to which the infant absorbs them is less clear. Limited reports have not suggested adverse pregnancy outcomes in women whose partners were exposed to anti-TNF therapies at the time of conception. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab and belimumab are limited and their use in pregnancy cannot currently be recommended.

AB0371 Clinical Significance of Anti-Adalimumab Antibodies in Rheumatoid Arthritis, Ankylosing Spondilitis and Psoriasic Arthritis

Background The generation of antidrug antibody (ADAb) is increasingly recognised as a mechanism explaining the failure of anti-TNF drugs in chronic inflammatory diseases. Objectives We designed a prospective, multicentre study on antibodies against adalimumab (anti-ADA) in a cohort of patients treated with adalimumab and affected with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriasic arthritis (PsA), to evaluate their clinical significance. Methods Fifty-eight consecutive patients were enrolled from four Italian Rheumatology Centres. Twenty-one (36.2%) were affected by RA, 22 (37.9%) by AS and 15 (25.9%) by PsA respectively. Anti-ADA antibodies were tested using ELISA commercial kits, kindly provided by Technogenetics, Italy, following the manufacters instructions. Moreover, anti-nuclear antibodies (ANA), anti-dsDNA antibodies, anti-estraible nuclear antigen (anti-ENA) and anti-phospholipid antibodies (aPL) were determined. Detection was made at baseline, 4, 12 and 24 weeks of therapy, respectively. Also, clinimetric (DAS28, BASDAI, BASFI, ASAS20) and serological (rheumathoid factor [RF], anti citrullinated cyclic peptides [ACPA] data were collected at the same intervals. Results The prevalence of anti-ADA, was 6/21 (28.6%) in RA, 4/22 (18.2%) in AS and 1/15 (6.7%) in PsA patients. Ten of the eleven anti-ADA (90.9%) occurred within the first month of therapy. There was a significant association between anti-ADA and lack of response and/or loss of drug efficacy in RA (OR 2.7, 95% CI: 1.5 - 4.9, p=0.0009), in AS (OR: 2.03, 95% CI 1.1 - 3.6; p=0.02), and in PsA (OR: 743.2, 95% CI 44.30 – 12.468; p<0.0001), respectively. Also, was a significant association between the presence of anti-ADA and the development of adverse events (p<0.0001). Surprisingly, was found a significant association between the positivity of RF and/or ACPA antibodies and the absence of anti-ADA, OR: 0.25, 95% CI: 0.1-0.5, p<0.0001 and OR: 0.3, 95% CI: 0.1-0.6, p=0.0008, respectively. The presence of ANA or anti-ENA was significantly associated with the development of anti-ADA (OR: 2.56, 95% CI 1.42-4.63, p=0.002 and OR: 4.56, 95% CI 2.39-8.67 p<0.0001). While, there was no significantly association between the presence of aPL antibodies and the presence of anti-ADA. No patient developed signs and/or symptoms of connective tissue disease or thrombosis during treatment with ADA. Conclusions Our study suggests that anti-ADA antibodies may be considered a predictor of the clinical response to ADA and the occurrence of adverse events. It would therefore justified to incorporate the determination of anti-ADA in the monitoring of patients with RA, AS and PsA treated with ADA. In the course of therapy with ADA may also be helpful the determination of ANA and anti-ENA in view of their association with anti-ADA. It remains to confirm whether patients positive for ACPA, because of the association with the absence of anti-ADA, may have a better response to treatment with ADA. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5938

Clinical value of anti-domain I-β2Glycoprotein 1 antibodies in antiphospholipid antibody carriers. A single centre, prospective observational follow-up study

BACKGROUND There seems to be a clear correlation between antibodies against domain I (anti-DI) of β2Glycoprotein I and severe clinical profiles in antiphospholipid syndrome (APS) patients. We investigated the clinical significance of anti-DI antibodies in a cohort of aPL carriers. METHODS One hundred and five carriers persistently positive for IgG anti-β2Glycoprotein 1 antibodies (a-β2GPI) and/or IgG anticardiolipin (aCL) and/or lupus anticoagulants (LAC) were tested for the presence of anti-DI antibodies using the QUANTA Flash® Beta2GPI-Domain I chemiluminescence immunoassay. RESULTS Anti-DI antibodies were detected in 44 aPL carriers (41.9%) and they were significantly associated to triple aPL positivity (LAC plus IgG a-β2GPI plus IgG aCL antibodies). Isolated LAC and a-β2GPI antibodies were significantly associated to anti-DI negative aPL carriers. During a 82.2 month mean follow-up, ten aPL carriers (9.5%) developed a first thrombotic event so becoming APS patients. Anti-DI antibodies, triple aPL positivity, thromboembolic risk factors and autoimmune disorders significantly prevailed in carriers becoming APS. Logistic regression analysis showed that anti-DI positivity was an independent risk factor for thrombosis. CONCLUSIONS Anti-DI antibody positivity can be considered a new risk factor predictive of the first thrombotic event in aPL carriers, instead, negative anti-DI may be useful to identify low-risk aPL carriers.

THU0325 Long-Term Outcome of Patients with Primary Antiphospholipid Syndrome: A Retrospective Multicenter Study

Background Data on the long-term outcome in primary antiphospholipid syndrome (PAPS) patients are still very limited. Objectives To assess the long-term frequency of recurrences, organ damage, severe comorbidities, mortality and evolution in connective tissue disease (CTD) in PAPS patients. Methods Medical records of PAPS patients followed in 6 centers for ≥15 years were retrospectively reviewed. Chi square for categorical and Student t test for continuous variables were used. P<0.05 was considered significant. Results One hundred and fifteen patients (88% females) followed between 1983 and 2014 with a mean age at diagnosis of 33 (±10) years and mean follow-up of 19 (±3.5) years were studied. Fifty-one patients (44%) had at least a thrombotic event during follow-up for a total of 75 events and an annual incidence of 3.5%. Thromboses were more frequent in patients with previous thrombotic history (p:0.002,OR:4.8, 95%CI:1.6–14.7). There was a tendency towards anticoagulant treatment being not protective against recurrences (p:0.063). Six patients (5%) had a catastrophic event. Fifty-two women had 87 pregnancies, successful in 78% of cases. Twenty-nine percent of patients had functional damage. Damage was significantly associated with a thrombotic history (p:0.004,OR:13.9,95%CI:1.8–288.4) and to arterial events (p<0.001,OR:7.9,95%CI:2.7–24.3) especially stroke, but not to demographics, serology or treatment. Twenty-four major bleeding episodes were recorded in 18 patients, all on anticoagulants. Severe infections affected 6 patients (5%) with 1 fatality. A solid cancer was diagnosed in 8 patients (7%). One patient (1%) with a chronic bowel ischemia died for sepsis. Eleven percent of patients developed a CTD and 14% another autoimmune disease. Conclusions Despite therapy, a high proportion of patients experienced new thrombotic events,while pregnancy outcome was significantly improved. Organ damage developed in a significant proportion of patients and was associated with arterial events. The risk of evolution in CTD has to be considered. Disclosure of Interest None declared