BackgroundIncreased activity of the type I interferon (IFN) pathway is central to the pathogenesis of SLE. Blocking the type I receptor may reduce SLE activity more effectively than inhibiting IFN-α alone.ObjectivesEfficacy and safety of anifrolumab were assessed in a Phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate to severe SLE (the MUSE study).Methods305 patients were treated for 48 weeks with intravenous anifrolumab (300 mg or 1000 mg) or placebo, in addition to standard-of-care medications. Randomization was stratified by SLE Disease Activity Index 2000 (SLEDAI-2K) score (<10 or ≥10), oral corticosteroid (OCS) dose (<10 or ≥10 mg/day), and IFN gene signature status (high vs. low) based on a 4-gene expression assay. The primary endpoint was the percentage of patients achieving an SLE Responder Index [SRI(4)] response at Day 169 with sustained reduction of OCS (<10 mg/day and ≤Day 1 dose from Day 85 to 169).ResultsThe primary endpoint was met by more anifrolumab-treated patients [placebo vs. 300 mg vs. 1000 mg: 17.6%, 34.3% (p=0.014), 28.8% (p=0.063)] with greater effect sizes observed in the 75% of patients who had a high baseline IFN signature [13.2%, 36.0% (p=0.004), 28.2% (p=0.029)]. At Day 365 more anifrolumab-treated patients achieved SRI(4) responses [40.2%, 62.6%, (p<0.001), 53.8%, (p=0.043)], BILAG-based Composite Lupus Assessment (BICLA) [25.7%, 53.5% (p<0.001), 41.2% (p=0.018)], modified SRI(6) [28.4%, 49.5% (p=0.002), 44.7% (p=0.015)], and SLEDAI-2K ≤2 [17.6%, 35.4% (p=0.004), 32.7% (p=0.012)]. Major clinical response (BILAG “C” or better in all domains at Day 169 maintained to Day 365) was achieved by 6.9%, 19.2% (p=0.012), and 17.3% (p=0.025) of patients. BILAG “A” flares were reported in more placebo- vs. anifrolumab-treated patients (16.7%, 9.1%, 10.6%). In patients with baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score ≥10, more anifrolumab-treated patients attained a ≥50% reduction by Day 365 [30.8%, 63.0% (p=0.013), 58.3% (p=0.077)]. In patients with ≥8 swollen and ≥8 tender joints at baseline more anifrolumab-treated patients achieved ≥50% decrease in joint count [48.6%, 69.6% (p=0.038), 64.6% (p=0.156)]. Although steroid tapering was not mandated, OCS reduction to ≤7.5 mg/d at Day 365 was achieved by 26.6%, 56.4%, and 31.7% of patients. The observed benefits were driven by results in the IFN-high subpopulation (figure). Median suppression of 21 IFN-regulated genes was ∼90% for both doses of anifrolumab. Patients in the placebo group had the lowest incidence of Herpes zoster (2.0%, 5.1%, 9.5%) and cases reported as influenza (2.0%, 6.1%, 7.6%); there were no differences in the incidence of serious adverse events (18.8%, 16.2%, 17.1%). The incidence of infusion-related reactions was similar (5.9%, 2.0%, 3.8%).ConclusionsAnifrolumab significantly reduced disease activity across all clinical endpoints. Enhanced effects in IFN-high patients support the pathobiology of this treatment strategy.AcknowledgementFunded by MedImmu...

Summary Moderate (greater than 20 units) and high (greater than 80 units) IgG anticardiolipin antibody (aCL) titres are strongly predictive for recurrent thrombosis and early myocardial infarction in non-diabetic subjects. We have tested the hypothesis that the excess risk of myocardial infarction in diabetic subjects relates to the presence of aCL by measuring the frequency and titre of aCL in two groups of diabetic subjects and in 2500 healthy controls. One non-diabetic subject (0.04%) had low (5-20 units) IgG aCL titres. Seven out of 126 diabetics without cardiovascular disease (5.6%) and 9 out of 79 diabetics who were either myocardial infarction survivors or who had angiographically-proven coronary artery disease (11.4%) had low aCL titres (P less than 0.01 for comparison of either diabetic group with controls, and P less than 0.1 for comparison between diabetic groups). One subject in each diabetic group, but no non-diabetics, had moderate IgM aCL titres. No subjects had high aCL titres. Diabetics have an increased frequency of low aCL titres which may relate to macrovascular disease. Macrovascular disease in diabetics is not associated with moderate or high aCL titres.

BackgroundAs reported elsewhere, anifrolumab was evaluated in a Phase IIb study of SLE patients with moderate to severe disease activity, in which 305 patients received intravenous infusions of anifrolumab (300 mg, 1000 mg) or placebo every 4 weeks for 1 year. Both doses demonstrated increased rates of reduction in global disease activity, although a more favorable risk-benefit profile was observed with the 300-mg dose.ObjectivesTo compare the impact of anifrolumab on individual organ domains in patients with moderate to severe SLE who participated in the Phase IIb study.MethodsAt Week 52, changes from baseline in organs domain activity were assessed using the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index 2000 (SLEDAI-2K). Improvement in a BILAG organ domain was defined as the transitioning from “A” or “B” to a lower score. Improvement in a SLEDAI domain required a lower score at Day 365 compared with baseline in at least one of its components.ResultsThe majority of patients had baseline involvement of the mucocutaneous and/or musculoskeletal domains of SLEDAI-2K and BILAG. Compared with placebo, a greater percentage of patients in the anifrolumab-treated group improved in these frequently involved organs: [Mucocutaneous: SLEDAI-2K: placebo 38/100 (38.0%) vs. 300 mg 61/99 (61.6%; p<0.001) vs. 1000 mg 51/102 (50.0%; p=0.082); BILAG: 24/87 (27.6%) vs. 49/84 (58.3%; p<0.001) vs. 33/82 (40.2%; p=0.069); Musculoskeletal: SLEDAI-2K: 42/99 (42.4%) vs. 55/97 (56.7%; p=0.032) vs. 50/98 (51.0%; p=0.197); BILAG: 47/95 (49.5%) vs. 64/94 (68.1%; p=0.005) vs. 54/91 (59.3%; p=0.149)]. Trends suggesting potential benefits were observed in most of the other less frequently active domains including SLEDAI-2K cardiorespiratory, vascular, hematological, and constitutional, and BILAG cardiorespiratory and constitutional domains. Of those patients who had involvement in the SLEDAI-2K immunological domain at baseline [positive anti-double-stranded-DNA (anti-dsDNA) and/or low complement level], a greater number of patients in the anifrolumab groups [placebo: 4/53 (7.5%); 300 mg: 9/43 (20.9%; p=0.068); 1000 mg: 18/59 (30.5%; p=0.004)] had lower scores at Day 365, representing a normalization of anti-dsDNA and/or hypocomplementemia. However, among patients who had a normal anti-dsDNA and/or normal complements at baseline a slightly greater number of patients treated with 300 mg anifrolumab had an increase in the score representing the development of a new anti-dsDNA or hypocomplementemia compared with baseline [placebo: 7/79 (8.9%); 300 mg: 11/82 (13.4%), 1000 mg: 6/79 (7.6%)].ConclusionsAnifrolumab treatment resulted in greater rates of improvement than placebo in multiple organs, with greatest impact seen with 300 mg anifrolumab.AcknowledgementFunded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UKDisclosure of InterestJ. Merrill Grant/research support from: MedImmune; Genentech/Roche, Consultant for: MedImmune, Genentech/Roche, Neovacs, R. Furie Consultant for: MedImmune,...

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Background Certain immunosuppressive agents are used in pregnancy in SLE patients to prevent flare and ensure optimal outcome for mother and child. There is little literature regarding long term outcomes of children.US data suggested a link between azathioprine(AZA) and infection1, and between anticardiolipin antibodies(abs) and developmental delay2 have been suggested. Objectives To assess if potential risk factors including maternal disease, autoantibodies, immunosuppression or other medication exposure influence health and behaviour of children. The following will be addressed:1)Does exposure to AZA in pregnancy &/or lactation increase risk of serious infections defined as requiring hospital assessment in the exposed children 2)Do immunosuppressive drugs or anti-phospholipid abs increase risk of developmental problems (delay±special needs±attention deficit disorder(ADD)±special educational needs). Methods A cross sectional, retrospective study recruited women with 4 SLE ACR criteria attending 8 specialist UK clinics with pregnancy data for children under 17yrs born after maternal SLE diagnosis. A standard questionnaire developed for this multi-centre study and used in US was used to collect data. Potential factors influencing infection and developmental problems, assessed were AZA, prednisolone, hydroxychloroquine, aspirin or heparin use in pregnancy, antiphospholipid syndrome, lupus anticoagulant &/or anticardiolipin (IgG&/orIgM) abs. Potential confounders assessed were pregnancy duration, pre-eclampsia, intra-uterine growth restriction, low birth weight, child age at assessment, maternal age at delivery, disease duration, prior renal biopsy and smoking. Results Complete data was available for 288 children born alive to 200 women: 66% Caucasian, 15% South Asian, 10% Afro-Caribbean,1% Chinese, 1% Hispanic 4% other and 4% not stated. The median (range) age of women at delivery was 32 (19-44) yrs, and duration of maternal disease was 6 (0-27) yrs. Infections were reported in 45(16%) of children. The odds ratio (OR) for infection in children with exposure to AZA was 1.63 (95%CI 0.84-3.15, p=0.15). In total 14(4%) of children were reported to have developmental delays, 7(2.5%) special needs, 3(1%) ADD and 6(2%) special educational needs. OR for developmental problems with AZA exposure was 1.22, 95%CI 0.44-3.42, and if mothers had antiphospholipid abs was 0.73, 95%CI 0.22-2.35. The age of child at assessment was associated with a small increased risk of developmental problems OR 1.15, 95%CI 1.05-1.26, p=0.003. No other potential risk factors were associated with infections or developmental problems. Conclusions No risk factors were identified for infection requiring hospital assessment, and only age of child at assessment was associated with increased risk of developmental problems. This study provides data to counsel women with SLE. References Akhtaret al. Maternal Anticardiolipin Affects Childhood Development.A&R.2008.57:9,443 Marderet al. In utero AZA exposure and increased utilization of special education...