Chiara Grava

Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity

In women diagnosed as having category I primary obstetric antiphospholipid syndrome, clinical characteristics and the risk of subsequent thromboembolic events and further unsuccessful pregnancy has not been clearly documented. Women with unexplained obstetric complications and no definite autoimmune systemic diseases were tested for lupus anticoagulant (LA), IgG/IgM anticardiolipin (aCL) and IgG/IgM anti-human beta2-Glycoprotein I (abeta2GPI) antibodies and diagnosed as having primary antiphospholipid syndrome (APS) in classification category I on the basis of more than one laboratory criteria present in any combination. Characteristics at the time of diagnosis and risk factors for subsequent clinical events during a mean follow-up of 6.3 years were evaluated. Fifty-three of 600 women studied were found to fulfil obstetric criteria and had more than one positive laboratory test at the time of diagnosis. All the women were aCL and abeta2GPI positive, and 16 were also LA positive. This latter group (triple positivity) had distinct features and had more frequently experienced previous thromboembolism (OR = 122.5, 95% CI 16-957, p < 0.001). They also had an increased rate of late pregnancy loss (OR = 16.2, 95%CI 0.9-292, p = 0.01), and a higher IgG abeta2GPI titer at diagnosis (median, 25(th) and 75(th) percentile were 118, 37-962, vs. 23, 18-32, respectively, p < 0.0001). During follow-up, the rate of thromboembolic events was significantly higher in the group of women with triple positivity and/ or previous thromboembolism (OR = 57.5, 95% CI 2.7-1160, p = 0.0004) which were the only independent predictors of TE in the multivariate model. Recurrent pregnancy loss took place in seven out of 47 women who had a new pregnancy. Triple positivity and/or previous thromboembolism were again the only independent markers (OR = 34.4, 95% CI 3.5-335.1, p = 0.003) of an unsuccessful new pregnancy. In conclusion, in primary APS with pregnancy morbidity in classification category I, quite different groups of patients may be identified on the basis of laboratory tests. Triple positivity and/or a history of thromboembolism predict new TE events and new unsuccessful pregnancies.

A combination therapy protocol of plasmapheresis, intravenous immunoglobulins and betamethasone to treat anti-Ro/La-related congenital atrioventricular block. A case series and review of the literature.

OBJECTIVES The aim of this report was to evaluate the efficacy and safety of a combined treatment protocol used to treat 2nd and 3rd degree anti-Ro/La-related congenital atrioventricular block (CAVB). METHODS Six consecutive women diagnosed with 2nd degree (three cases) or 3rd degree block (three cases) between 2009 and 2011 referred to our outpatient clinic underwent a combination therapy protocol composed of weekly plasmapheresis, fortnightly 1g/kg intravenous immunoglobulins (IVIG) and daily betamethasone (4mg/day) throughout pregnancy. IVIG (1g/kg) treatment in the neonates was begun at birth and administered every fifteen days until passive maternal antibodies became undetectable. RESULTS The fetuses affected with 2nd degree block (cases 1, 2 and 3) reverted to a normal atrioventricular conduction after combined therapy, while those with a 3rd degree block remained stable (case 4), showed an increase in the ventricular rate (case 5) or an improvement in cardiac function (case 6). None of the fetuses with 3rd degree CAVB had other cardiac complications such as cardiomyopathy or fetal hydrops. The follow-up of the children affected with 2nd degree CAVB revealed a complete regression of the block in cases 1 and 3, and no signs of relevant worsening in case 2. The infants affected with 3rd degree block (cases 4, 5, and 6) remained stable and until now only one has required a pacemaker at the age of 10months. CONCLUSIONS If these results are confirmed by large-scale studies, this protocol could lead to improved outcomes in the treatment of this devastating disease.

Congenital heart block not associated with anti-Ro/La antibodies: comparison with anti-Ro/La-positive cases.

Objective. To study anti-Ro/La-negative congenital heart block (CHB). Methods. Forty-five fetuses with CHB were evaluated by analysis of anti-Ro/La antibodies using sensitive laboratory methods. Results. There were 9 cases of anti-Ro/La-negative CHB; 3 died (33.3%). Only 3 (33.3%) were complete in utero and 5 (55.5%) were unstable. No specific etiology was diagnosed. Six infants (66.6%) were given pacemakers. There were 36 cases of anti-Ro/La-positive CHB. All except 2 infants (94.4%) had complete atrioventricular block in utero. Ten died (27.8%), one (2.7%) developed severe dilated cardiomyopathy, and 26 (72.2%) were given pacemakers. Conclusion. Nine of the 45 consecutive CHB cases (20%) were anti-Ro/La-negative with no known cause. They were less stable and complete than the anti-Ro/La positive cases.

The clinical relevance of early anti-adalimumab antibodies detection in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: A prospective multicentre study.

OBJECTIVES To evaluate the relevance of anti-adalimumab (anti-ADA) antibodies (Abs) and their relationship with clinical/laboratory features in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS Fifty-eight patients affected with RA, AS and PsA were prospectively enrolled. Clinical/laboratory characteristics, disease activity, anti-ADA, anti-nuclear (ANA), anti-double strand (ds)DNA, anti-extractable nuclear antigens (anti-ENA) and anti-phospholipid Abs (aPL) were evaluated at baseline, 4, 12 and 24 weeks of adalimumab treatment. RESULTS Anti-ADA Abs were observed in 11/58 (19%) patients; they were detected within the 4th week of therapy in 90.9% of the positive subjects. Anti-ADA positivity was associated with significantly lower mean adalimumab serum levels (P<0.05). Treatment failure was observed in 20/58 (34.5%) patients and was significantly associated with anti-ADA Abs (P<0.05). Mean adalimumab serum levels were significantly lower in patients with treatment failure than in the responders one, both in the whole cohort (P<0.01) and in the group of anti-ADA positive patients (P<0.01). Adverse events happened more often in anti-ADA positive then in anti-ADA negative patients (27.3% vs 14.9%). CONCLUSIONS Anti-ADA abs could be considered an early marker associated to a poor clinical response to adalimumab treatment. Routine ANA/anti-ENA/aPL monitoring did not reveal as useful tools to predict the development of anti-ADA abs.

Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome.

Abstract Background: Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies have begun to be considered potentional biomarkers for antiphospholipid syndrome (APS). This cohort study investigate the role of aPS/PT antibodies as a risk factor for severe APS by evaluating the association between those antibodies and clinical/laboratory profiles of APS. Methods: Plasma/serum samples from 197 APS patients, 100 healthy subjects and 106 patients with autoimmune diseases were collected. IgG/IgM aPS/PT antibodies were assayed using commercial ELISA kit. Results: Prevalences of IgG and IgM aPS/PT (p<0.0001 and p=0.0009, respectively) and their titres (p<0.0001 and p=0.0002, respectively) were significantly higher in thrombosis/pregnancy group with respect to pregnancy morbidity alone. Prevalences of IgG and IgM aPS/PT (p<0.0001 and p=0.0004, respectively) and their mean levels (p=0.0001 for both) were significantly higher in the prematurity linked to life-threatening obstetric complications group with respect to miscarriage group. There was a significant relationship between IgG and IgM aPS/PT (p=0.001 and p=0.0002) and their mean levels were higher (p=0.0004 and p=0.0002, respectively) in the thrombotic microangiopathy group, considered a milestone manifestation of catastrophic APS. The relationship between IgG and IgM aPS/PT was significant and mean levels were higher in triple positive antiphospholipid antibody patients than in double and single positivity ones (p<0.0001 for all). Conclusions: APS/PT antibodies were associated to severe thrombosis, severe pregnancy complications inducing prematurity, and vascular microangiopathy, all generally associated to high risk APS forms requiring strong therapy.

Apheresis in high risk antiphospholipid syndrome pregnancy and autoimmune congenital heart block

In the first part a prospective cohort study was reported to evaluate the efficacy and safety of a treatment protocol including plasma exchange (PE) or PE plus intravenous immunoglobulins (IVIG) or immunoadsorption (IA) plus IVIG administered in addition to conventional therapy to 22 pregnant women with high-risk APS. The results indicate that PE or IA treatments administered along with IVIG and conventional antithrombotic therapy could be a valuable and safe therapeutic option in pregnant APS women with triple antiphospholipid antibody positivity along with a history of thrombosis and/or one or more severe pregnancy complications. In the second part the efficacy and safety of PE combined with IVIG and steroids were evaluated for the treatment of 10 patients with autoimmune congenital heart block (CHB) by comparing maternal features, pregnancy outcome and side effects with those of 24 CHB patients treated with steroids only. The patients treated with the combined therapy showed a statistically significant regression of 2nd degree blocks, an increase in heart rate at birth and a significantly lower prevalence of pacing in the first year of life. Moreover, no side effects were observed except for a few steroid-related events. If these results are confirmed by large-scale studies, the apheretic procedures could lead to improved outcomes in the treatment of these devastating diseases.

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

AB0410 Pregnancy and Anti-TNFα Drugs: Experience of Four Centres

Background The introduction of biologic therapies has significantly improved the outcome of inflammatory rheumatic diseases. As most of these diseases affect women and men in childbearing age there is concern about safety of biologic drugs during reproduction and pregnancy. Objectives To evaluate the effects of anti-TNFα agents on pregnancy and foetal outcome. Methods We conducted a retrospective multicentre study of 24 women and 2 men with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA), respectively. They were treated with anti-TNFα agents prior to conception or until conception/during pregnancy. Data were collected from four Centres (Belluno, Padua, Trento and Udine). A 28-question chart abstraction form was filled by the treating rheumatologist. The primary outcome was the occurrence of congenital malformations. Secondary outcomes were the rate of premature birth (defined as <37 weeks of gestation), small for gestational age (defined as <10th percentile) and the occurrence of vaccine complications. Results Until to 31st December 2014, a total of 32 pregnancies were registered, including one twin pregnancy; 5 women had multiple pregnancies. Twenty-four/32 (75%) pregnancies were exposed to anti-TNFα agents at conception or during pregnancy; 21 of these (87.5%) pregnancies occurred following maternal exposure and 3 (12.5%) following paternal exposure. While 8/32 (25%) pregnancies, following leaflet recommendations, had suspended the therapy before conception. An overview of pregnancies following maternal exposure is reported in table 1. One infant was diagnosed with congenital diaphragmatic hernia and obstructive megaureter; the mother was exposed to adalimumab (ADA) at conception and developed preeclampsia at 33 week of gestation (WG). One infant was diagnosed with cystic fibrosis at 3 months of age; the mother was exposed to etanercept (ETN) at conception. One mother exposed to certolizumab (CZP) at conception underwent caesarean section at 35 WG due to preterm premature rupture of membranes. Two mothers exposed to ETN at conception developed a vanishing syndrome and a post-partum infection, respectively. There was no significant difference concerning gestational age and birth weight, both between the group exposed to anti-TNF-alpha at conception and that exposed before conception and, between the groups exposed to different anti-TNFα agents. Seventeen out of 21 infants (80.9%) underwent vaccinations according to national schedule. None of them have any vaccine complications. The pregnancies following paternal exposure were all in ETN. All pregnancies ended in live births. There was one infant with intrauterine growth restriction. The baby was admitted for 14 days to the neonatal intensive care unit for respiratory distress. Conclusions Maternal exposure to anti-TNFα at conception was not associated with an increased risk of congenital malformation and/or with other adverse outcomes. Also the exposure to anti-TNFα in men at time of conception was not associated with any adverse outcome in their partners or newborns. Disclosure of Interest None declared