Ian Giles

The efficacy of repeated treatment with B-cell depletion therapy in systemic lupus erythematosus: an evaluation

OBJECTIVEnSince 2000, we have given B-cell depletion therapy (BCDT) with rituximab to 76 patients with active SLE refractory to standard immunosuppression. Twenty-four of these patients have now received repeated cycles of BCDT. The aims of the study were to: (i) assess the efficacy and safety of repeated cycles of BCDT in treating refractory SLE; and (ii) assess whether retreatment produced a more sustained clinical response.nnnMETHODSnBCDT was administered using CYC 750 mg, methylprednisolone 125-250 mg and rituximab 1 g given intravenously on two occasions, 2 weeks apart. Patients were reviewed at 1-2 monthly intervals and disease activity assessed using the BILAG activity index and serological markers. Clinical response was categorized as complete or partial remission, or no response, based on the change in BILAG scores.nnnRESULTSnEighteen patients had sufficient data for detailed analysis. All were female; mean age 29.9 years; mean duration of follow-up 58.7 months. Two patients died during follow-up and there were two infusion reactions. Disease activity was significantly reduced after both cycles of BCDT at 6 months. More patients achieved disease remission after the second cycle (82 vs 61% first cycle), which was maintained in 65% at 12 months (vs 39% first cycle). The time to disease flare was significantly longer after the second cycle (P < 0.001) and 33% of our patients have still not flared to date following retreatment (mean follow-up 24.5 months).nnnCONCLUSIONnRepeated cycles of BCDT with rituximab are effective in treating refractory SLE and has a favourable safety profile. Retreatment may produce a more sustained clinical response.

Brain abnormalities in newly diagnosed neuropsychiatric lupus: Systematic MRI approach and correlation with clinical and laboratory data in a large multicenter cohort

OBJECTIVESnTo describe brain magnetic resonance imaging (MRI) abnormalities in newly diagnosed neuropsychiatric lupus (NPSLE). To correlate them with clinical and laboratory data.nnnMETHODSnThis retrospective cross-sectional study included patients presenting NPSLE undergoing brain MRI within 6 months after onset between 2003 and 2012. Clinical and laboratory data were recorded. MRI findings were defined as inflammatory-like, large-vessel disease (LVD), and small-vessel disease (SVD); SVD was classified as white-matter hyperintensities (WMH), recent small subcortical infarcts, lacunes, microbleeds, and brain atrophy.nnnRESULTSnWe included 108 patients (mean 40.6 ± 14.2 years; range 14-77), 91.7% women. The most frequent syndromes were headache (28.5%), cerebrovascular disease (15.5%), seizure (15.5%), and cognitive dysfunction (11.4%). Brain abnormalities were found in 59.3%. SVD was the most common (55.6%), followed by LVD (13%) and inflammatory-like lesions (6.5%). The most frequent SVD findings were WMH (53.7%), atrophy (18.5%), microbleeds (13.7%) and lacunes (11.1%). Cerebrovascular syndrome correlated with LVD (p = 0.001) and microbleeds (p = 0.002), cognitive dysfunction with WMH (p = 0.045) and myelopathy with inflammatory-like lesions (p = 0.020). Low C4 and CH50 correlated with inflammatory-like lesions (p < 0.001, p = 0.019) and lupus anticoagulant with WMH (p = 0.018), microbleeds (p = 0.002) and atrophy (p = 0.008).nnnCONCLUSIONSnVascular disease is the hallmark of NPSLE. Certain syndromes and immunological patterns are prone to more extensive brain damage. MRI could provide significant clinical information and insights into the pathological substrate.

Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren's Syndrome

To investigate whether rituximab, an anti–B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögrens syndrome (SS).

[Accepted Manuscript] Randomized Controlled Trial of Rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren's Syndrome.

To investigate whether rituximab, an anti–B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögrens syndrome (SS).

Pregnancy Outcomes in Patients with Psoriatic Arthritis.

To the Editor: nnHistorically, pregnancy has been considered to have a beneficial effect upon inflammatory arthritis, with around 75% of women with rheumatoid arthritis (RA) reportedly improving. These findings were mostly from retrospective studies, which lacked objective measures of disease activity1. Modern prospective studies using validated measures of disease activity reveal less impressive ameliorative effects of pregnancy on inflammatory disease activity, reporting that around 50% of women with active RA improve during pregnancy2. Further, it is now recognized that active disease in women with inflammatory arthritis is associated with adverse pregnancy outcomes3. Most studies, however, have focused on patients with RA and there is much less information on disease activity and pregnancy outcomes in women with psoriatic arthritis (PsA).nnTherefore, we carried out a retrospective analysis of all patients with … nnAddress correspondence to Dr. I.P. Giles, University College London Hospital, 235 Euston Road, London, NW1 2BU, UK. E-mail: i.giles{at}ucl.ac.uk

OP0084 Oxidation of β2-Glycoprotein I is Strongly Associated with the Presence of Anti-Domain I Antibodies in Patients With Antiphospholipid Syndrome

Background Beta-2 glycoprotein I (β2GPI) represents the major antigenic target for antiphospholipid antibodies (aPL), the hallmark of antiphospholipid syndrome (APS). β2GPI contains five homologous domains, with domain I (DI) being identified as the main antigenic epitope for pathogenic anti-β2GPI (aβ2GPI). It has been reported that APS patients show an elevated amount of total β2GPI as compared with healthy donors and other autoimmune disease control groups. Moreover, in healthy individuals, β2GPI mainly exists in its biochemically reduced form whilst the post-translational oxidized structure (fish-hook linear configuration) is elevated in patients with APS. Antibodies targeting β2GPI-DI (aDI) represent a key pathogenic sub-population of aPL, thus their detection may allow the identification of patients at highest clinical risk. Objectives Our hypothesis is that the different redox state of β2GPI, from reduced (circular) to oxidised (linear), might be responsible for the exposure of DI, thus providing the antigenic drive for the aDI antibodies. However, no study has investigated the association between the circulating oxidized form of β2GPI and the presence of aDI in APS patients. Methods Serum samples from 40 patients who fulfilled the classification criteria for APS were tested (34 primary and 6 secondary APS). A sandwich ELISA for quantifying total β2GPI levels within serum was performed for all samples. An in-house standard (consisting of pooled serum from 10 healthy controls) was used to obtain a standard curve in each ELISA. Biochemically reduced β2GPI was detected via labelling free thiols within serum proteins with a biotinylated free-thiol binding reagent and then, via coating on a streptavidin plate, detecting the presence of labelled β2GPI with an aβ2GPI antibody, based on published methods. Then samples were screened for IgG aDI, aβ2GPI and anti-cardiolipin (aCL). Results The positivity for aDI, aβ2GPI and aCL IgG was 60%, 75% and 80% respectively. The relative proportion of reduced β2GPI was expressed as a percentage of that observed in the in house-standard after correction for the total amount of β2GPI. A significant negative correlation was observed between proportion of reduced β2GPI and aDI levels (Spearman coefficient r = -0.409, p=0.008) and aCL titre (r = -0.317, p=0.045). There was no significant correlation between proportion of reduced β2GPI and aβ2GPI (r = -0.059, p=0.713). Conclusions The strong association between the oxidative state of β2GPI and aDI positivity supports the hypothesis that modulation of the redox state of β2GPI affects the production of antibodies against the DI epitope, which become exposed in the oxidised protein. However, it remains to be proven if the exposure of DI within the oxidised (hence linearized) form of β2GPI acts as the antigenic drive for development of aDI autoantibodies or whether the presence of these antibodies stabilizes the antigen-antibody complex maintaining the linear configuration of the molecule. Disclosure of Interest None declared

Mechanisms of Antiphospholipid Antibody-Mediated Thrombosis

Antiphospholipid antibodies (aPL) are key elements responsible for thrombosis in antiphospholipid syndrome (APS) patients. Current evidence indicates that aPL have wide-ranging effects on vascular cells, coagulation factors, and regulators of the coagulation cascade that produce a procoagulant phenotype. However, the molecular mechanisms underlying these processes remain incompletely understood. Inflammation serves as a necessary link between the observed procoagulant phenotype and thrombus development, with the complement cascade, toll-like receptors, and cytokines playing key roles. In this chapter, we outline the mechanisms that contribute to thrombosis in APS. We also review the facets of this topic for which there is no consensus among experts in the field, for instance, the relative importance of various mechanisms in the precipitation of thrombosis. Finally, we outline ongoing studies, namely, those presented at the recent 15th International Congress on aPL and our vision of the future direction of APS thrombosis research.

Clinical and Prognostic Significance of Non-criteria Antiphospholipid Antibody Tests

Classification criteria for antiphospholipid syndrome (APS) require IgG and IgM isotypes of the anticardiolipin antibodies (aCL), anti-β2 glycoprotein I antibodies (aβ2GPI), and/or the lupus anticoagulant (LA) to satisfy the laboratory criterion for disease definition. However, over the past 20 years, several other non-criteria antiphospholipid antibodies (aPL) directed to other proteins of the coagulation cascade (i.e., prothrombin and/or phosphatidylserine–prothrombin complex), to some domains of β2GPI, or to the anticoagulant activity of annexin A5, have been proposed. The Laboratory Diagnostics Task Force at the 14th International Congress on aPL (Rio de Janeiro, Brazil, 2013) highlighted several non-criteria assays. However, there was consensus that further studies are necessary to obtain high-quality evidence defining their role as risk predictors. The task force reviewed the literature and conducted new studies between 2013 and 2016; the conclusions were presented at a special session during the 15th International Congress on aPL (www.apsistanbul2016.org, North Cyprus, September 2016). This paper updates our recommendations.

Fertility and pregnancy in systemic lupus erythematosus

Systemic Lupus Erythematosus (SLE) is a chronic multisystem autoimmune disease with a heterogeneous pattern of clinical and serological manifestations. The predilection for women, particularly of childbearing age, combined with improved survival has led to increasing numbers of women with lupus considering pregnancy. Management of pregnancy in SLE however, requires careful planning and close medical and obstetric monitoring to ensure optimal outcomes. This review, discusses possible causes of subfertility, issues regarding contraception and family planning as well as management of lupus during pregnancy and outcomes in pregnant women with SLE.

THU0318 The Pregnancy Experience of 85 Women with SLE Followed in A Specialist Lupus Clinic Compared To The General Population: Table 1

Background SLE affects women of childbearing age. Research suggests that patients with SLE have similar rates of pregnancy as other women but a higher rate of pregnancy loss [1]. Parity may be reduced due to infertility eg. secondary to antiphospholipid syndrome, pregnancy loss or personal choice. Concerns over teratogenic medication, disability and child health have been cited as personal reasons [2]. Objectives Our aim was to carry out a retrospective analysis of the pregnancy experience of women with SLE followed up for a mean of 18 years in a specialist clinic. Methods Pregnancy data were collected on 85 women with SLE via questionnaire between June and December 2015. Questions focused on parity, number of pregnancies, miscarriages, stillbirths, termination of pregnancy and number of live births. Questions related to pregnancy complications included pre-eclampsia, intrauterine growth retardation (IUGR), abruption placenta, gestational diabetes, caesarean sections (CS) and preterm labour <37 weeks. Data on smoking and serology were obtained from the medical records. Results Of 85 women with SLE, the mean age was 45 years and mean follow-up was 18±11 years. Ethnicity was 53% white, 10.5% Asian, 27% Afro-Caribbean and 9% other. 20% were current/previous smokers. 43.5% were anti-Ro positive. 14% were LA positive, 15% were aCL positive and 8% were anti-β2GPI positive. The questionnaire results are summarised in Table 1, with comparison to UK population figures where they are available.Table 1 SLE (n=85) UK population average Never pregnant 36.5% Unknown No children 47% 20% at age 45* Miscarriage rate 22% 15–20% Elective TOP 20% ≈36% by age 45 Average family size (for the 45 who had children) 1.5 1.82 children Number with >3 children 11% 14.3%* *Office of National Statistics UK. Among the 45 parous women, there were 83 live births. 80% (36/45) had 1–2 children. 15% had 3 (7/45) children and 4% (2/45) had 4 children. No patient had more than 4 children. Miscarriages occurred in 22% (19/85); 18% (8/45) had preterm labour, 4.4% (2/45) had hypertension during pregnancy, 9% (4/45) had CS, 4.4% had low birth weight. Other adverse pregnancy outcomes included placental abruption (2.2%), ectopic pregnancy (2.2%), IUGR (2.2%) and stillbirth (twins) (2.2%). Conclusions The major finding of this study was that almost half the respondents had no children, more than double what one would expect in UK women of the same mean age. This was primarily due to never having been pregnant rather than increased rate of TOP or miscarriage. Further research into the social and/or medical reasons for this avoidance of pregnancy is required. Pregnancy morbidity amongst those who had been pregnant was common especially miscarriage and pre-term labour. References Petri, M. and J. Allbritton, Fetal outcome of lupus pregnancy: a retrospective case-control study of the Hopkins Lupus Cohort. J Rheumatol, 1993. 20(4): p. 650–6. Clowse, M.E., et al., Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken), 2012. 64(5): p. 668–74. Disclosure of Interest None declared