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The current treatment paradigm in lupus nephritis consists of an initial phase aimed at inducing remission and a subsequent remission maintenance phase. With this so-called sequential treatment approach, complete renal response is achieved in a disappointing proportion of 20–30% of the patients within 6–12 months, and 5–20% develop end-stage kidney disease within 10 years. Treat-to-target approaches are detained owing to uncertainty as to whether the target should be determined based on clinical, histopathological, or immunopathological features. Until reliable non-invasive biomarkers exist, tissue-based evaluation remains the gold standard, necessitating repeat kidney biopsies for treatment evaluation and therapeutic decision-making. In this viewpoint, we discuss the pros and cons of voclosporin and belimumab as add-on agents to standard therapy, the first drugs to be licenced for lupus nephritis after recent successful randomised phase III clinical trials. We also discuss the prospect of obinutuzumab and anifrolumab, also on top of standard immunosuppression, currently tested in phase III trials after initial auspicious signals. Undoubtably, the treatment landscape in lupus nephritis is changing, with combination treatment regimens challenging the sequential concept. Meanwhile, the enrichment of the treatment armamentarium shifts the need from lack of therapies to the challenge of how to select the right treatment for the right patient. This has to be addressed in biomarker surveys along with tissue-level mapping of inflammatory phenotypes, which will ultimately lead to person-centred therapeutic approaches. After many years of trial failures, we may now anticipate a heartening future for patients with lupus nephritis.

The presence of antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE) has been associated with increased risk of thrombotic and/or obstetric manifestations.1 The mechanism of action of belimumab is inhibition of the binding of soluble circulating B lymphocyte stimulator to its target receptors on B cells. Belimumab use was associated with autoantibody reduction, such as antidouble-stranded DNA, anti-Sm and anticardiolipin (aCL) antibodies in some previous reports.2 The objective of this study was to assess the effect of belimumab 10 mg/kg versus placebo on aPL titres using pooled data from two large randomised SLE-controlled trials (BLISS-76 (NCT00410384) and BLISS-52 trial (NCT00424476)). Levels of three isotypes of aCL antibodies (IgG, IgM and IgA) were assessed at baseline and at each visit. There we no available data on antiβ2GPI antibodies and lupus anticoagulant. The median (IQR) aCL titre, and the titre change from baseline (Δ titre) at 3, 6 and 12 months was compared between treatment arms by Mann-Whitney U test. At a second step, we undertook a random intercept mixed-effects model with the change of aCL titres from baseline as the dependent variable and treatment arm as a fixed effect. Time was added in the model, while the interaction of treatment and time was also assessed. The models were further adjusted for potential confounders (age, sex, concomitant immunosuppressive therapy, concomitant antimalarials, baseline prednisolone dose). Due to a potential effect of antimalarials on aCL titres, stratified analyses were also performed. We also assessed the …

Primary Sjogren syndrome (pSS) may be complicated by type II cryoglobulinaemia in approximately 5%–20% of patients. pSS is actually the first aetiology of type II cryoglobulinaemia,1 the latter being associated with development of vasculitis, extraglandular involvement, increased risk of B-cell lymphoma and decrease in survival. Rituximab, a monoclonal anti-CD20 antibody, is frequently used in the treatment of cryoglobulinaemia. B-cell activating factor (BAFF), also known as B-lymphocyte stimulator, plays a key role in the survival and activation of B cells. An elevation in BAFF levels occurs after B-cell depletion induced by rituximab.2 It is the consequence of a decrease in B cells that are the most important reservoir of cells expressing the BAFF receptor and of an upregulation of BAFF mRNA.3 The association of belimumab with rituximab could be synergistic and is currently evaluated in pSS and systemic lupus erythematosus.4 We report three cases of patients with refractory cryoglobulinaemic vasculitis complicating pSS successfully treated by the combination of an anti-CD20 therapy followed by belimumab (table 1, …

ObjectiveWe evaluated the discriminant capacity of the Lupus Low Disease Activity State (LLDAS) in post-hoc analysis of data from the BLISS-52 and BLISS-76 trials of belimumab in systemic lupus erythematosus (SLE).MethodsLLDAS attainment, discrimination between belimumab and placebo arms, and the effects in subgroups with high disease activity at recruitment were evaluated at week 52 using appropriate descriptive statistics, χ2test and logistic regression.ResultsAt week 52, for belimumab 10 mg/kg, 17.0% and 19.3% of patients who achieved a Systemic Lupus Erythematosus Responder Index-4 also attained LLDAS in BLISS-52 and BLISS-76, respectively. Significantly more patients attained LLDAS on belimumab 10 mg/kg compared with placebo (12.5% vs 5.8%, OR 2.32, p=0.02 for BLISS-52; 14.4% vs 7.8%, OR 1.98, p=0.04 for BLISS-76). In a subgroup analysis, the difference in week 52 LLDAS attainment between belimumab 10 mg/kg and placebo was greater in patients who had higher disease activity at baseline, compared with the overall group.ConclusionsLLDAS was able to discriminate belimumab 10 mg/kg from placebo in the BLISS-52 and BLISS-76 trials. Our findings support the validity of LLDAS as an outcome measure in SLE clinical trials.

ObjectivesThe study (206347) compared organ damage progression in patients with systemic lupus erythematosus (SLE) who received belimumab in the BLISS long-term extension (LTE) study with propensity score (PS)-matched patients treated with standard of care (SoC) from the Toronto Lupus Cohort (TLC).MethodsA systematic literature review identified 17 known predictors of organ damage to calculate a PS for each patient. Patients from the BLISS LTE and the TLC were PS matched posthoc 1:1 based on their PS (±calliper). The primary endpoint was difference in change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score from baseline to 5 years.ResultsFor the 5- year analysis, of 567 (BLISS LTE n=195; TLC n=372) patients, 99 from each cohort were 1:1 PS matched. Change in SDI score at Year 5 was significantly lower for patients treated with belimumab compared with SoC (−0.434; 95% CI –0.667 to –0.201; pConclusionsPS-matched patients receiving belimumab had significantly less organ damage progression compared with patients receiving SoC.

Background:Belimumab (BEL), a recombinant human monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), is approved for the treatment of systemic lupus erythematosus (SLE). Clinical studies have yielded varying incidence rates of mortality and adverse events of special interest, such as malignancies, thereby necessitating large-scale, long-term assessment following BEL exposure.Objectives:To assess all-cause mortality and new primary malignancies during post-treatment Year 2 follow-up in adult patients with active, autoantibody-positive SLE who received intravenous (IV) BEL or placebo (PBO), plus standard therapy in the 52-week double-blind treatment period of the ongoing BASE trial.1Methods:This was a post-treatment follow-up of the Phase 4, double-blind study (BASE1; GSK Study BEL115467; NCT01705977), which randomised 4019 adults with active SLE and receiving standard therapy to BEL (10 mg/kg IV) or PBO on Days 0, 14, 28, and monthly thereafter until Week 48. All patients (including those who discontinued BEL before the end-of-treatment phase) were contacted by phone annually (+/-30-day time window). Rates of mortality and new primary malignancy are summarised for Year 2 follow-up, presented by the treatment received during the 52-week double-blind treatment period (Year 1).Results:Baseline patient characteristics and disease activity collected at the start of the study, evaluated in patients with Year 2 follow-up were similar to the overall Year 1 study population. Cumulatively by Year 2 follow-up, 10.7% and 9.5% of patients had been exposed to commercial BEL in the BEL and PBO groups, respectively. Cumulative follow-up adjusted mortality and malignancy rates (per 100 patient years) were lower in the BEL vs PBO Year 1 treatment group (Table 1).Conclusion:Year 2 follow-up results of BASE, the largest clinical trial of SLE to date,1 provide continued support for the BEL safety profile. No new BEL safety concerns were identified in patients with active, autoantibody-positive SLE receiving standard therapy.Funding: GSKReferences:[1]Sheikh SZ, et al. Lancet Rheum. 2020 (ePub ahead of print) doi.org/10.1016/S2665-9913(20)30355-6Table 1.Year 2 post-treatment* follow-up mortality and new primary malignancy rates by study treatment during Year 1BELPBOTotalYear 1 as-treated populationN=2002N=2001N=4003Year 1 deaths, n (%)13 (0.65)22 (1.10)35 (0.87)Year 1 new primary malignancies, n (%)9 (0.45)10 (0.50)19 (0.47)Year 2 (as-treated in Year 1) populationN=1681N=1666N=3347Year 2 deaths by MedDRA SOC, n (%)9 (0.54)21 (1.26)30 (0.90)Cardiac disorders2 (0.12)6 (0.36)8 (0.24)Infections and infestations4 (0.24)2 (0.12)6 (0.18)Uncoded1 (0.06)3 (0.18)4 (0.12)General disorders/administration site conditions1 (0.06)2 (0.12)3 (0.09)Gastrointestinal disorders1 (0.06)1 (0.06)2 (0.06)Neoplasms02 (0.12)2 (0.06)Other05 (0.30)†5 (0.15)Cumulative deaths by Year 2 follow-up, n (%)22 (1.10)43 (2.15)65 (1.62)Incidence rate per 100 patient years0.601.180.89Year 2 new primary malignancies by MedDRA SOC, n (%)3 (0.18)4 (0.24)7 (0.21)Neoplasms2 (0.12)4 (0.24)6 (0.18)Hepatobiliary disorders1 (0.06)01 (0.03)Cumulative malignancies by Year 2 follow-up, n (%)12 (0.60)14 (0.70)26 (0.65)Patient incidence rate per 100 patient years0.340.400.37*Patients in the post-treatment follow-up period are no longer receiving study treatment; †1 event/patient: blood/lymphatic system, musculoskeletal/connective tissue, nervous system, psychiatric, and renal/urinary disorders.MedDRA, Medical Dictionary for Regulatory Activities; SOC, system organ class.Acknowledgements:Medical writing assistance was provided by Katalin Bartus, PhD, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Saira Sheikh Grant/research support from: Pfizer, Morton Scheinberg Consultant of: GSK, Pfizer, Alnylam, AbbVie, PTC Therapeutics, James Cheng-Chung Wei Consultant of: TSH Biopharm, AbbVie, BMS, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer, Sanofi-Aventis and UCB pharma, Grant/research support from: AbbVie, Amgen, Astellas, BMS, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer Sun and UCB, Dana Tegzová: None declared, William Stohl Consultant of: GSK, Grant/research support from: GSK, Pfizer, Gilead, Tamara Mucenic Speakers bureau: Novartis, Janssen, BMS, AbbVie, Pfizer, Roche, Grant/research support from: GSK, Janssen, Roche, Eli Lilly, Gilead, UCB, Raj Punwaney Shareholder of: GSK, Employee of: GSK, Regina Kurrasch Shareholder of: GSK, Employee of: GSK, Julia Harris Shareholder of: GSK, Employee of: GSK, Saima Muzaffar Shareholder of: GSK, Employee of: GSK, Sofia Fernandes Shareholder of: GSK, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, Andrew Liu Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Background:BLISS-LN (GSK Study BEL114054; NCT01639339), the largest lupus nephritis (LN) study to date, showed that intravenous (IV) belimumab (BEL) + standard therapy (ST) improved outcomes compared with ST alone in patients (pts) with active LN.1Objectives:To assess additional safety and efficacy data of BEL + ST in pts with LN in a 6-month open-label (OL) phase beyond 2 years of double-blind (DB) treatment in BLISS-LN.Methods:In this OL phase, eligible completers of the DB phase received monthly BEL 10 mg/kg IV + ST for 6 months. Endpoints: safety; Primary Efficacy Renal Response (PERR; uPCR ≤0.7; eGFR no worse than 20% below OL baseline eGFR or ≥60 ml/min/1.73 m2; no prohibited medications) and Complete Renal Response (CRR; uPCR 2; no prohibited medications) at OL Week 28; proportion of pts with SLEDAI score Results:We enrolled 257 pts (57.4% of pts in BEL114054) and treated 255 pts. All treated pts were included in the safety population (123 pts switched from placebo [PBO] to BEL; 132 pts remained on BEL). Efficacy was assessed in the safety population, excluding 1 pt due to non-compliance (mITT population; PBO to BEL: 122 pts; BEL to BEL: 132 pts). 96.5% of pts completed the OL phase; 3.5% withdrew, mainly due to adverse events (AE; 2.0%).Overall, 168/255 (65.9%) pts had ≥1 AE (76/123 [61.8%] PBO to BEL pts; 92/132 [69.7%] BEL to BEL pts); 15/255 (5.9%) pts had ≥1 serious AE (5/123 [4.1%] PBO to BEL pts; 10/132 [7.6%] BEL to BEL pts); 1 (0.8%) pt died in the PBO to BEL group.Proportions of PERR and CRR responders increased from OL baseline to OL Week 28 (Table 1. below)Proportions of pts who attained SLEDAI scores In pts with autoantibodies at OL baseline, anti-dsDNA and anti-C1q levels decreased from OL baseline to OL Week 28 in both groups. Among pts with low C3/C4 levels at OL baseline, C3/C4 levels increased from OL baseline to OL Week 28 in both groups (Table 1. below)Conclusion:In this OL phase of BLISS-LN, proportions of PERR and CRR responders increased in both the BEL-naïve and BEL-experienced groups; and no new safety signals were observed. Improvements in biomarker levels were observed, especially in pts who switched from PBO to BEL.Funding:GSK.References:[1]Furie R, et al. N Engl J Med. 2020;383(12):1117-28.Table 1.Responses at OL baseline and OL Week 28 (mITT population, N=254)OL baseline*OL Week 28PBO to BEL(n=122)BEL to BEL(n=132)PBO to BEL(n=122)BEL to BEL(n=132)n122132118122PERR, n (%)73 (59.8)†93 (70.5)†79 (66.9)91 (74.6)CRR, n (%)44 (36.1)†63 (47.7)†57 (48.3)76 (62.3)SLEDAI score n122132120122Responders, n (%)44 (36.1)†64 (48.5)†40 (33.3)64 (52.5)Prednisone-equivalent dosen122132121128≤5 mg, n (%)59 (48.4)78 (59.1)60 (49.6)75 (58.6)≤7.5 mg, n (%)62 (50.8)85 (64.4)66 (54.5)83 (64.8)Anti-dsDNA (IU/ml)‡n85648161Median (IQR) levels107.0 (49.0, 212.0)65.5 (42.5, 126.5)--Median (IQR) % change from baseline---30.2 (-46.3, -6.8)-10.7 (-27.2, 9.1)Anti-C1q (U/ml)§n64605854Median (IQR) levels71.7 (36.6, 167.5)47.1 (33.0, 75.7)--Median (IQR) % change from baseline---23.0 (-41.5, 0.5)-16.5 (-33.0, 6.1)C3 (mg/dl)‖n45374435Median (IQR) levels78.0 (72.0, 83.0)80.0 (71.0, 84.0)--Median (IQR) % change from baseline--6.2 (-4.2, 14.6)4.7 (-4.8, 16.9)C4 (mg/dl)‖n18121811Median (IQR) levels7.5 (6.0, 8.0)7.0 (7.0, 8.5)--Median (IQR) % change from baseline--23.6 (11.1, 37.5)11.1 (0.0, 57.1)*DB Week 104 visit and the OL baseline visit were the same visit; †Post hoc analyses; ‡Among anti-dsDNA positive pts at OL baseline (≥30 IU/ml); §Among anti-C1q positive pts at OL baseline (≥22.2 U/ml); ‖Among pts with low C3 (Acknowledgements:Medical writing assistance was provided by Olga Conn, PhD, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Richard Furie Consultant of: GSK, Grant/research support from: GSK, Brad H Rovin Consultant of: GSK, Frederic Houssiau Consultant of: GSK, Grant/research support from: UCB, Gabriel Contreras Consultant of: Genentech, Merck, Grant/research support from: Genentech, Merck, Paula Curtis Shareholder of: GSK, Employee of: GSK, Anuradha Madan Shareholder of: GSK, Employee of: GSK, Angela Jones-Leone Shareholder of: GSK, Employee of: GSK, Mohamed Okily Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Background:LN is still a severe manifestation of Systemic lupus erythematosus (SLE) and multitarget therapy is needed to control the disease especially in refractory cases.Objectives:To evaluate renal response in SLE patients with glomerulonephritis (GN) treated with Belimumab in real-life setting.Methods:Patients with proteinuria >0.5 g/24 h and/or active sediment at baseline enrolled in a multicentre Italian cohort of SLE patients (BeRLiSS study), treated with monthly iv Belimumab 10 mg/kg plus standard of care were considered in this study. Complete renal response (CRR) was defined as proteinuria 2 and no rescue therapy. Primary efficacy renal response (PERR) was defined as proteinuria ≤0.7 g/24 h, eGFR ≥60ml/min/1.73m2 and no rescue therapy. Prevalence and predictive factors of CRR and PERR at 12 and 24 months after Belimumab initiation were analyzed by multivariate logistic regression analysis.Results:A total of 91 patients were considered in this study, 79 female, mean age 40.51±9.03 years, mean disease duration 12.18±8.15 years, median follow-up time after Belimumab initiation 22 months. Twenty patients had baseline proteinuria ≥0.5 2 at baseline. Immunosuppresants were taken by 70 (76.9%) patients: 47 micofenolate, 15 azathioprine and 5 ciclosporine. Sixty patients (65.9%) were on antimalarials. During follow-up 34 (37.4%) patients achieved CRR. Among them 5 (14.7%) patients relapsed and 29 (85.3%) patients maintained remission. Mean time to achieved CRR was 9.71±5.91 months.High levels of baseline proteinuria were a negative independent predictor of CRR and PERR at 6 months (OR 0.044 CI95% 0.006-0.320 p=0.002 and OR 0.232 CI95% 0.091-0.596 p=0.002) and 12 months (OR 0.029 CI95% 0.002-0.556 p=0.019 and OR 0.056 CI95% 0.009-0.327 p=0.001). High levels of baseline creatinine were a negative independent predictor of renal response. Renal response at 6 months was a strong predictive factor of renal response at 12 and 24 months.Conclusion:Belimumab is an effective add-on therapy in the treatment of GN in real-life practice setting.Disclosure of Interests:None declared

BackgroundIntravenous belimumab plus standard of care (SoC) is approved in the USA and Europe for treatment of active, autoantibody-positive systemic lupus erythematosus (SLE).MethodsThis phase III, multicentre, randomised, double-blind, placebo-controlled study (BEL113750; NCT01345253) was conducted in 49 centres across China, Japan and South Korea (May 2011–September 2015). Patients with SLE were randomised 2:1 to intravenous belimumab 10 mg/kg or placebo, plus SoC, every 4 weeks until Week 48. The primary endpoint was the SLE Responder Index (SRI) 4 response rate at Week 52. Secondary endpoints were the percentage of patients with ≥4 point reduction in Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), SRI7, time to first severe flare and number of days prednisone (or equivalent) dose ≤7.5 mg/day and/or reduced by 50% from baseline. Safety was assessed.ResultsThe modified intent-to-treat population included 677 patients (belimumab n=451, placebo n=226). At Week 52, the SRI4 response rate was higher with belimumab versus placebo (53.8% vs 40.1%; OR: 1.99 (95% CI: 1.40, 2.82; P=0.0001)). The percentages of patients with a ≥4 point reduction in SELENA-SLEDAI and an SRI7 response were significantly greater for belimumab versus placebo. Patients in the belimumab group had a 50% lower risk of experiencing a severe flare than those receiving placebo (P=0.0004). In patients with baseline prednisone dose >7.5 mg/day, there was a significant reduction in steroid use favouring belimumab (P=0.0228). The incidence of adverse events was similar between groups.ConclusionsIn patients with SLE from North East Asia, belimumab significantly improved disease activity, while reducing prednisone use, with no new safety issues.

Background:In Italy, the use of belimumab has been authorized since 2013, in patients with active systemic lupus erythematosus (SLE) with positive anti–double-stranded DNA and low C3 or C4 levels, despite standard therapy. Belimumab is effective in reducing disease activity and number of flares and in blocking damage progression. To our knowledge, no data are available on dose tapering of belimumab in SLE patients chronically treated with it.Objectives:The aim of this retrospective study was to analyse prevalence of tapering in a single cohort and to evaluate disease activity after tapering.Methods:Patients, who received intravenous belimumab (10mg/kg) for at least 12 months between June 2013 and December 2020 were enrolled. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC-SDI), Physician Global Assessment (PGA), C3 and C4 levels, and prednisone daily dose were recorded at baseline and every six-months. Follow-up was stopped when patients switched to subcutaneous belimumab or when it was discontinued for more than 6 months (interrupted). Dose tapering was defined as the prolongation of the regular dose interval, after initial treatment based on the registered dosage.Results:Between June 2013 and December 2020, 48 patients received intravenous belimumab for at least 12 months (100% Caucasians, 94% females). All patients received standard belimumab dosage of 10mg/Kg every 4 weeks. Fourteen (29.1%) of 48 patients lengthened the dosing interval to 5 weeks; a subsequent lengthening of the interval occurred in 7 patients every 6 weeks and in 1 patient belimumab was gradually tapered to every 13 weeks.Twelve months (T12) after belimumab introduction, 3 patients (6.2%) were receiving a tapered dosage; at T24, 9 out of the 37 (24.3%), at T36 9 out of 21 (42.8%), and at T48 8 out of 18 (44.4%). Differences in disease activity, damage, concomitant medications, disease duration at belimumab introduction (baseline) were evaluated among patients that maintained the standard interval versus the group that received a tapered dose. Notably, no differences were found among the two groups (standard dose vs tapering) concerning median age at baseline (41, IQR 31-47.5 vs 38, IQR 32.2-51.5), disease duration (median 11, IQR 7.2-16 vs 9, IQR 5.5-14.5), median prednisone daily dosage (7.1mg, IQR 5-11.9 versus 11mg, IQR 7.6-17.5) and median SLEDAI-2K (8, IQR 6-9.75 vs 8, IQR 5-10). Differences in concomitant medications or clinical manifestations are reported in Figure 1A.Among the group that received the standard dose, 7 patients discontinued the treatment (20.6%), specifically 2 renal flares and one adverse event occurred. Whereas, in the reduced dose group, 2 discontinuations occurred (14.3%) due to a pregnancy and a renal flare. Noteworthy, the patient with the renal flare resumed subcutaneous belimumab 12 months after the flare. Finally, the disease activity was analysed in the 12 months after the first drug reduction (Figure 1B-E), with no sign of worsening of evaluated parameters (Figure 1B-1E), but with a significant reduction of steroids and SLEDAI-2K, 6 months after tapering.Conclusion:In our single retrospective cohort, we have demonstrated that belimumab tapering seems to be safe and not associated with a worsening disease activity over the following months. However, further studies are required to identify eligibility criteria and to determine the optimal dose-tapering strategy both for the intravenous and the subcutaneous formulations.Figure 1.Disclosure of Interests:None declared

Background:Clinical features of systemic lupus erythematosus may differ significantly in various regions and are frequently associated with the ethnicity of patients.Objectives:The aim of this study was to compare clinical features and treatment of patients with systemic lupus erythematosus in the Russian Federation (RF), Kirgizstan and Kazakhstan in real clinical practice.Methods:1102 SLE pts who fulfilled SLICC 2012 criteria were enrolled into the study. Disease activity was evaluated by the SLEDAI-2K, and chronic damage by the Systemic Lupus International Collaborating Clinics Damage Index score (SDI).Results:400/600/102 Lupus pts from RF, Kirgizstan and Kazakhstan respectively were studied. Pts were predominantly female (91%/93%/98%) with a mean±SD age of 34,2±11,5/35,07±12,2/33,8±10,5 years (p=0,36; p=0,96) respectively. The mean disease duration (Мe) in RF/ Kazakhstan was 6 [3;12]/ 5[2;9] years (p=0,15), in Kirgizstan- 2[0,6; 7] years(p≤0,05). Kazakh pts (p=0,00) have higher disease activity (SLEDAI 2K) 17,6±8,8 than Kirghiz pts 15,1±8,3 and Russian pts 9,4±8,1. The higher SLICC damage index 2,39±1,61was in Kazakh pts (p=0,00) as compared to the Russian. Clinical features of 1102 patients with systemic lupus erythematosus in the Russian Federation (RF), Kirgizstan and Kazakhstan are shown in Table 1. Among the Kirghiz, most of the patients were with Neuropsychiatric disorders (33%), vasculitis (27%), serositis (49%) and lupus nephritis (41%). Patients in RF and Kazakhstan were more likely to have arthritis (60%/80%) and mucocutaneus lesions (44%/74%) respectively.Russian/Kirghiz/ Kazakh pts received corticosteroids per os with duration (Me) 48[18; 106] /24[7,2; 84]/ 37[13; 84] months. The mean±SD dosage was 17,8±12,0/23,2± 19,9/12,33±9,8 mg per day. Аmong cytostatic drugs, patients in Kirgizstan were prescribed more often cyclophosphamide (64%) and methotrexate (27%). They were prescribed mofetila micofenolate much less frequently (4%) than patients from Russia (20%) and Kazakhstan (46%). Prescription of cyclophosphamide, azathioprine and methotrexate in the Russian and Kazakhstan pts was approximately of the same frequency and ranged from 10 to 23%. Hydroxychloroquine was obtained in 67%/26%/51% Russian/Kirghiz/ Kazakh pts respectively. Disability benefits in RF included payment for biological therapy. Lupus patients in Kirgizstan and Kazakhstan bought biological drugs at their own expense. In RF rituximab was administrated in 34% cases and belimumab -in 10%. In Kirgizstan and Kazakhstan rituximab was administrated in 2% and 6% respectively.Table 1.Clinical Features of 1102 Patients with Systemic Lupus Erythematosus in the Russian Federation (RF), Kirgizstan and KazakhstanClinical featuresRussian Federationn (%)Kyrgyztann (%)Kazakhstann (%)Pyrexia52(13%)276 (46%)15 (15%)Neuropsychiatric68 (17%)198 (33%) 34(33%)Mucocutaneus176 (44%)396 (66%) 75 (74%)Vasculitis40 (10%)162 (27%)4 (4%)Arthritis240 (60%)282 (47%) 81(80%)Myocarditis16 (4%)78 (13%)-Serositis52 (13%)294 (49%)12 (12 %)Lupus nephritis116 (29%)246 (41%) 24 (24%)Leukopenia≤3х10936 (9%)96 (16%)6 (6%)Trombocytopenia ≤ 100X 10 912 (3%)90(15%)5(5%)Anti dsDNA ≥20 Ед\мл276 (69%)198 (33%)80 (80%)Low complement200 (50%)324 (54%)6 (6%)Conclusion:Significant differences have been revealed in the Kirghiz patients as compared to those of the RF and Kazakhstan. Disease activity in vital organs was more often revealed in the Kirghiz patients: neuropsychiatric disorders, vasculitis, serositis and lupus nephritis. As a result, they received a higher mean corticosteroids dose and cyclophosphamide was administered more often. Prescription of biological therapy was limited by a high cost of such sort of drugs. In spite of this fact, the highest SLICC damage index was demonstrated by the Kazakh cohort (2,38 score, while the lowest of merely 0,79) was in the Kirghiz cohort.Disclosure of Interests:None declared

Background:Belimumab inhibits the activity of the soluble cytokine BLyS (B lymphocyte stimulator) and is recommended for use in moderate refractory systemic lupus erythematosus (SLE). A recent randomised controlled trial reported that Belimumab improves the outcomes for patients with lupus nephritis when used with standard therapy.Objectives:We present two cases of lupus nephritis that developed in SLE patients without pre-existing renal disease shortly after commencing treatment with Belimumab.Methods:Both patients are Afro-Caribbean females with similar immunological profiles, including ANA, dsDNA, anti-Sm, anti- Ro and anti-RNP antibodies. The first was 59 years old with a long standing diagnosis of SLE since 1996 that had required previous Cyclophosphamide for neuropsychiatric lupus. She was most recently taking Hydroxychloroquine, Mycophenolate and Prednisolone having previously failed with Azathioprine twice. Belimumab was commenced in February 2020 due to worsening arthritis, mouth ulcers, pleuritis and systemic features associated with a significant rise in her dsDNA and low complement. Her SLEDAI score was 13. After six months of treatment she developed proteinuria for the first time. Her urine protein creatinine ratio (uPCR) was measured at 205mg/mmol and a subsequent renal biopsy revealed features of active Class IV and V lupus nephritis. Belimumab was changed to Rituximab. Mycophenolate was stopped due to persistent neutropenia and Tacrolimus was introduced instead. After 5 months treatment her uPCR is now 33mg/mmol.The second patient was 37 years old with a recent diagnosis of SLE in 2018. She presented with inflammatory arthritis, oral and nasal ulcers, and cytopenia. She responded poorly to Azathioprine and was intolerant of Mycophenolate. Her most recent treatment was Hydroxychloroquine and Prednisolone. She was commenced on Belimumab in February 2020 due to active mucocutaneous and musculoskeletal features of lupus with a SLEDAI score of 12. The mucocutaneous features of lupus responded well but she developed proteinuria seven months later, and by November 2020 her uPCR was 149mg/mmol. Belimumab was switched to Rituximab and initially her uPCR continued to rise but it has now fallen to 43mg/mmol.Results:The occurrence of new lupus nephritis soon after the initiation of Belimumab monotherapy has been reported previously and our cases raise further concerns. A prospective observational study recently reported significantly increased rates of new lupus nephritis developing in patients receiving Belimumab in addition to standard care compared to those receiving standard treatment. An association between Belimumab and the development of de novo lupus nephritis has not yet been conclusively established but it would create a significant challenge in how Belimumab is used and consented for in SLE, especially if it becomes more widely used to treat lupus nephritis. The mechanism by which Belimumab may increase the risk of, or trigger, lupus nephritis is currently unclear but may result from increased activity in BLyS associated pathways following the blockade of the BLyS pathway.Conclusion:These two cases raise questions about the role of using Belimumab in patients at risk of developing lupus nephritis. We therefore recommend caution in its use and recommend active monitoring of renal parameters especially in patients with poor clinical and serological response to Belimumab.References:[1]Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020; 383(12):1117-28[2]Sjöwall C, Cöster L. Belimumab may not prevent lupus nephritis in serologically active patients with ongoing non-renal disease activity. Scand J Rheumatol. 2014; 43(5):428-30[3]Staveri C, Karokis D, Liossis SN. New onset of lupus nephritis in two patients with SLE shortly after initiation of treatment with belimumab. Semin Arthritis Rheum. 2017; 46(6):788-790[4]Parodis I, Vital EM, Hassan SU, et al. De novo lupus nephritis during treatment with belimumab. Rheumatology. 2020; keaa796Disclosure of Interests:None declared

Background:BAFF and APRIL are TNF superfamily members that form homo- and heteromultimers that bind TACI and BCMA on B cells; BAFF also binds BAFF-R. BAFF and APRIL support B cell development, differentiation, and survival, particularly for plasmablasts and plasma cells, and play critical roles in the pathogenesis of B cell-related autoimmune diseases. In nonclinical models, inhibition of either BAFF or APRIL alone mediates relatively modest effects, whereas their co-neutralization dramatically reduces B cell function, including antibody production. Fc fusions of wild-type (WT) TACI (e.g. atacicept and telitacicept) target both BAFF and APRIL and have demonstrated promising clinical potential in e.g. systemic lupus erythematosus (SLE) and IgA nephropathy but have not yet clearly exhibited long-term and/or complete disease remissions.Objectives:To generate a dual BAFF/APRIL antagonist with inhibitory activity superior to WT TACI and BCMA and with the potential to improve clinical outcomes in B cell-mediated diseases.Methods:Our directed evolution platform was used to identify a potent variant TNFR domain (vTD) of TACI that exhibits significantly enhanced affinity for BAFF and APRIL as compared to WT TACI; this TACI vTD domain was fused to a human IgG Fc to generate the therapeutic candidate ALPN-303. ALPN-303 was evaluated for functional activity in: 1) human lymphocyte assays, 2) the NOD.Aec1Aec2 spontaneous model of Sjogren’s syndrome (SjS), 3) the bm12-induced mouse model of lupus, 4) the (NZB/NZW)F1 spontaneous model of lupus, and 5) preclinical rodent and cynomolgus monkey pharmacokinetic/pharmacodynamic studies.Results:ALPN-303 inhibited BAFF- and APRIL-mediated signaling in vitro in human lymphocyte assays, with significantly lower IC50 values than WT TACI-Fc and belimumab comparators. In all mouse models evaluated, administration of ALPN-303 rapidly and significantly reduced key lymphocyte subsets including plasma cells, germinal center B cells, and follicular T helper cells. ALPN-303 significantly reduced autoantibodies and sialadenitis in the spontaneous SjS model, inhibited glomerular IgG deposition in the bm12-induced model of lupus, and potently suppressed anti-dsDNA autoAbs, blood urea nitrogen levels, proteinuria, sialadenitis, kidney lesions, and renal immune complex deposition in the NZB/W lupus model. As compared to WT TACI-Fc, ALPN-303 exhibited higher serum exposure and significantly and persistently decreased titers of serum IgM, IgG, and IgA antibodies in mice and cynomolgus monkeys (Figure 1).Figure 1.ALPN-303 induces more potent suppression, as compared to WT TACI-Fc, of serum immunoglobulins following a single 9 mg/kg IV infusion (on Day 0; arrows) in female cynomolgus monkeys.Conclusion:ALPN-303 is a potent BAFF/APRIL antagonist derived from our directed evolution platform that consistently demonstrates encouraging immunomodulatory activity and efficacy in vitro and in vivo, superior in preclinical studies to anti-BAFF antibody and WT TACI-Fc. This novel Fc fusion molecule demonstrates favorable preliminary developability characteristics, including higher serum exposures and more potent immunosuppressive activities, which may enable lower clinical doses and/or longer dosing intervals than WT TACI-Fc therapeutics. ALPN-303 may thus be an attractive development candidate for the treatment of multiple autoimmune and inflammatory diseases, particularly B cell-related diseases such as SLE, SjS, and other connective tissue diseases. Preclinical development is underway to enable the initiation of clinical trials later this year.Disclosure of Interests:Stacey R. Dillon Shareholder of: Alpine Immune Sciences, Bristol Myers Squibb, Employee of: Alpine Immune Sciences, Bristol Myers Squibb, Lawrence S. Evans Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Katherine E. Lewis Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jing Yang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Mark W. Rixon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Joe Kuijper Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Dan Demonte Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Janhavi Bhandari Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Steve Levin Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Kayla Kleist Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Sherri Mudri Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Susan Bort Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Daniel Ardourel Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Michelle A. Seaberg Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Rachel Wang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Chelsea Gudgeon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Russell Sanderson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Martin F. Wolfson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jan Hillson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Stanford L. Peng Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences

Background:Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterised by persistent B-cell activation. Belimumab (BEL), a monoclonal antibody that inhibits B-lymphocyte stimulator, is approved in patients aged ≥5 years with active autoantibody-positive SLE; however, safety and efficacy data of BEL in older adults are limited.Objectives:Assess the safety and efficacy of BEL in older adults with SLE.Methods:A meta-analysis (GSK study 116559) was performed on the subpopulation of patients aged ≥65 years and compared with the overall population pooled from six controlled, repeat-dose (CRD) BEL trials in adults with SLE (GSK studies: 110752, 110751, LBSL02 [safety only], 112341, 113750, and 115471). Additional safety data were obtained from GSK study 115467.In each trial, patients were randomised to BEL or placebo (PBO) and received ≥1 treatment dose (GSK studies 110752 and 110751: intravenous [IV] BEL 1 or 10 mg/kg; LBSL02: IV BEL 1, 4, or 10 mg/kg; GSK study 112341: subcutaneous BEL 200 mg; GSK studies 113750, 115471, and 115467: IV BEL 10 mg/kg) plus standard therapy. Safety assessments included: incidence of serious adverse events (SAE), mortality and adverse events of special interest (AESI). The primary efficacy analysis for the CRD trials was the SLE Responder Index 4 (SRI4) response rate.Results:Older adults (CRD studies: N=63; study 115467: N=156) had lower disease activity and more organ damage compared with the overall populations, and a greater proportion were of white race compared with the overall population in the CRD studies. There were no clinically relevant differences in the incidence of SAE or death between older adults and the overall populations (Table 1). Rates of AESI (post-infusion/injection systemic reactions [PISR], serious infections of special interest, malignancies, psychiatric events) were generally similar or lower in older adults compared with the overall populations with no imbalances between BEL and PBO in older adults (Table 1). No malignancies were reported in older adults. The SRI4 response rate in older adults favoured BEL vs PBO (OR [95% CI], 1.49 [0.49, 4.58]), consistent with the overall populations of the individual CRD studies (110752 and 110751 pooled [10 mg/kg IV]: 1.68 [1.32, 2.15]; 112341: 1.68 [1.25, 2.25]; 113750: 1.99 [1.40, 2.82]; 115471: 1.42 [0.94, 2.15]).Conclusion:In patients with SLE, the safety and efficacy of BEL in older adults were generally consistent with the overall population and suggest a favourable benefit–risk profile. Due to the small number of older adults analysed, these data should be interpreted with caution.Funding:GSKTable 1.SAE, deaths, and AESIN (%)*Study 115467CRD studies†Older adults(N=156)Overall(N=4003)Older adults(N=63)Overall(N=4170)PBON=82BELN=74PBON=2001BELN=2002PBON=27BELN=36PBON=1355BELN=2815SAE9 (11.0)6 (8.1)222 (11.1)220 (11.0)5 (18.5)10 (27.8)230 (17.0)421 (15.0)Death‡1 (1.2)1 (1.4)11 (0.5)12 (0.6)006 (0.4)16 (0.6)AESI PISR§,‖,¶----02 (5.6)110 (8.1)286 (10.2) Serious PISR002 (8 (0.4)002 (0.1)13 (0.5)Infections of SI (opportunistic, herpes zoster, tuberculosis, sepsis)§02 (2.7)50 (2.5)36 (1.8)1 (3.7)097 (7.2)173 (6.1)Serious infections of SI02 (2.7)17 (0.8)17 (0.8)0017 (1.3)40 (1.4)Malignancies ex. non-melanoma skin cancer§005 (0.2)5 (0.2)002 (0.1)8 (0.3)Depression(inc. mood disorders /anxiety)/suicide/self-injury§,¶,**-‖---3 (11.1)3 (8.3)92 (6.8)210 (7.5)Serious depression/ suicide/self-injury01 (1.4)6 (0.3)18 (0.9)1 (3.7)05 (0.4)9 (0.3)*Patients counted once/category; †Pooled data from all studies except 115467; ‡Study 115467: fatal SAEs that started during on-treatment period; death may have occurred after period end. CRD studies: all deaths during double-blind period; §Per custom MedDRA query; ‖Occurring on/within 3 days of infusion/injection; ¶Study 115467: only serious PISR and serious depression/suicide/self-injury events collected; **Per standard MedDRA query.MedDRA, Medical Dictionary for Regulatory Activities; SI, special interestAcknowledgements:Medical writing assistance was provided by Helen Taylor, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:David d’cruz Speakers bureau: GSK, Consultant of: GSK, Eli Lilly, Gina Eriksson Shareholder of: GSK, Employee of: GSK, Yulia Green Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Objectives:To assess the efficacy of combined therapy with rituximab (RTM) and belimumab (BLM) in patients with active systemic lupus erythematosus (SLE).Methods:The study included 12 SLE pts (1М/11F) with severe (SLEDAI2K≥10 – 8pts.) and moderate (SLEDAI2KResults:8 pts demonstrated the decrease in clinical and laboratory SLE activity, starting from 3mo of follow-up. After the start of BLM infusions, a decrease in SLE activity was observed in all patients. Among them, 9 had SLEDAI-2K activity of less than 4 points (SLEDAI-2k Me 12 [9,5;17], after treatment of RTM and BLM 4[2;4]). Only one patient (№4) had a relapse of SLE, due to the omission of the BLM infusion. He was receiving standard GC doses. In dynamics, a decrease anti-double DNA titres (Me 101 [39;250]U/ml vs 19 [9;70] U/ml), С3 (0,44 [0,39;0,59]g/l vs 0,81 [0,72;0,87] g/l), С4 (0,06 [0,031;0,1] g/l vs 0,14 [0,13;0,14] g/l) was registered. The GC dose was reduced in most patients (tab. 1), but the previously prescribed immunosuppressive therapy continued. There were no cases of severe infection.Conclusion:Combination therapy allows to gain control over disease activity in short time, due to the effect of RTM, while added BLM provides further prolongation of the effect achieved, minimizing the risk of flare. The use of such therapy contributes to a rapid and effective reduction in the activity of the disease, normalization of laboratory markers of SLE (at to ds-DNA, C3, C4), the use of lower doses of oral GCs. This combination may be used as a method of choice in pts with severe SLE involving vital organs, and in persistent cutaneous-articular disease and high immunological activity.Table 1.Dose of oral glucocorticoids (prednisone), mg№ patientBefore the introduction of RTM, mg1st 7th injection of of BLM, mg7th injection of BLM, mg1202015↓27,555↓3555=4101010↓5555=6607,52,5↓↓↓7102,50↓↓↓810105↓92,52,52,5=1010105↓11000=12000=Disclosure of Interests:None declared

Background:While there have been advances in the therapy of systemic lupus erythematosus (SLE) in recent years, there have been no major new findings in SLE biomarkers [1, 2]. Type I interferon (IFN) plays a pivotal role in the pathogenesis of SLE [3]. In 2008, we first described CD169 / SIGLEC-1 (sialic acid-binding immunoglobulin-like lectin-1), an interferon-induced adhesion molecule on monocytes in SLE patients [4]. For over five years SIGLEC-1 has been routinely assessed in our clinic.Objectives:To evaluate and compare the diagnostic utility of the type I IFN induced SIGLEC-1 with established biomarkers in the initial diagnosis of the disease.Methods:We analyzed retrospectively 232 patients who were on suspicion of SLE at Charité University Hospital Berlin between October 2015 and September 2020. Patients underwent full clinical characterization, and biomarkers were determined in the routine laboratory. Based on the final diagnosis, we divided patients into two groups: A) initial diagnosis of SLE and B) Non-SLE mimicking condition.Results:In 76 patients (32.3 %) SLE was confirmed by fulfilling the EULAR / ACR 2019 classification criteria [5]. SIGLEC-1 was dramatically increased in patients with an initial diagnosis of SLE compared to patients without SLE (p 99.9 % and 0.2 %. We further aimed to compare not only the performance of the tests at a given cutoff but also across all possible measured values. Therefore, we conducted ROC curves analyses (see figure 1). The area under the curve (AUC) of SIGLEC-1 test was significantly higher than that of ANA test (AUC=0.88, p=0.031), C3 (AUC = 0.83, p=0.001), C4 (AUC=0.83, p=0.002), but not than that of the Anti-dsDNA ELISA (AUC=0.90, p=0.163).Conclusion:Our study shows that IFN activity is a hallmark at the onset of the disease and that the interferon biomarker SIGLEC-1 is valuable to rule out SLE in suspected cases.References:[1]Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, Enghard P, Richter U, Biesen R, Schneider U et al: Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med 2020, 383(12):1149-1155.[2]Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, Amoura Z, Yu X, Mok CC, Santiago MB et al: Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med 2020, 383(12):1117-1128.[3]Ronnblom L, Leonard D: Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med 2019, 6(1):e000270.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, Haupl T, Rudwaleit M, Riemekasten G, Radbruch A et al: Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum 2008, 58(4):1136-1145.[5]Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, Smolen JS, Wofsy D, Boumpas DT, Kamen DL et al: 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Annals of the Rheumatic Diseases 2019, 78(9):1151-1159.[6]Brinks R, Fischer-Betz R, Sander O, Richter JG, Chehab G, Schneider M: Age-specific prevalence of diagnosed systemic lupus erythematosus in Germany 2002 and projection to 2030. Lupus 2014, 23(13):1407-1411.Disclosure of Interests:None declared

Background:Belimumab (BLM), a recombinant human monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients with active severe systemic lupus erythematosus (SLE) and lupus nephritis (LN). There is clinical evidence that combining BLM with B cell depleting therapy can ameliorate disease activity in severe, refractory SLE patients1. Although BLM is a B cell directed therapy and has been shown to significantly decrease total B cells, flow cytometry observations suggest a rapid increase of circulating memory B cells (MBC)2.Objectives:To investigate dynamics of B-cell subsets in SLE patients treated with or without BLM, with a focus on assessing MBC characteristics.Methods:Extensive B cell subset phenotyping was performed by high-sensitivity (HS) flow cytometry (acquisition of 107 leukocytes; per EuroFlow protocols3) on samples from active LN or SLE patients with major organ involvement treated with standard of care (SOC) consisting of high dose steroids and mycophenolate mofetil combined with or without the addition of BLM. MBC gene expression profiles were characterized with single-cell RNA and V(D)J sequencing (ScRNA-SEQ).Results:By employing HS flowcytometry, we established that the absolute increase in circulating MBC in SLE and LN patients was significant for patients who initiated BLM (Figure 1). The increase was observed in a broad range of MBC subsets (Unswitched, IgG1+, IgG2+, IgA1+, IgA2+) at 2 and 4 weeks following initiation of BLM treatment. This rise in MBC could hypothetically be attributed to either proliferation of blood MBC, BLM induced migration of tissue-resident MBCs or BLM related retention of tissue-destined MBC in the blood. ScRNA-SEQ analysis of cell cycle gene-expression was performed and established in both groups a non-proliferating phenotype [in approximately ~94%] of MBC post-treatment, including absence of MKI67 as active proliferation marker. Clonal diversity analysis comparing week 2 with baseline revealed an unexpected decrease of the largest MBC clones in BLM, whereas no change in clonality was observed with SOC alone. Together these data indicate that proliferation is unlikely to be responsible for the observed increase in MBC by BLM. Furthermore, a clear difference was found in gene-expression levels between both treatment groups: BLM was responsible for the upregulation of 72 vs 10 genes in SOC, likewise 162 vs 32 genes were downregulated. Most importantly, a significant downregulation of the migration genes SELL (CD62L), CCR7, ITGB1, RAC2 and ICAM2, were specifically seen in BLM treated patients. This may reflect disrupted lymphocyte trafficking, preventing MBCs from transmigrating from the blood into tissue owing to reduced migration molecules, or preventing MBCs from being retained at the tissue level owing to reduction in tissue adhesion proteins.Conclusion:The addition of BLM to SOC significantly increases MBCs in patients with SLE independently of proliferation, accompanied by a strong modulation of gene expression, including reduced expression of migration markers pointing towards disrupted lymphocyte trafficking. These data may have important implications for improving treatment strategies in patients with LN or severe SLE, as a deeper depletion of autoreactive MBCs could be established by adding B-cell-depleting therapy after the initiation of BLM.Figure 1.Change in pre-germinal center and memory B cell counts from baseline to week 4 of patients with SLE or LN treated with SOC (n=8) or SOC+BLM (n=11).References:[1]Arends EJ et al. Long-term effects of combined B cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrol Dial Transplant. 2020 Jun 27 gfaa117.[2]Stohl W et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with SLE. Arthritis Rheum. 2012;64(7):2328-2337.[3]Blanco et al, Age-associated distribution of B and plasma cell subsets in peripheral blood - J Allergy Clin Immunol 2018 141 2208-2219.Disclosure of Interests:Eline J. Arends: None declared, Mihaela Zlei: None declared, Christopher M. Tipton: None declared, Zgjim Osmani: None declared, Sylvia Kamerling: None declared, Ton Rabelink: None declared, Ignacio Sanz: None declared, Jacques J.M. van Dongen Paid instructor for: BD Biosciences: Educational Services (fees for LUMC), Consultant of: BD Biosciences and Cytognos (fees for LUMC), Grant/research support from: GSK (flow cytometry studies for GSK BLISS-BELIEVE study NCT03312907), Cees van Kooten: None declared, Y.K. Onno Teng Consultant of: Aurinia provided financial compensation for consultancy, Grant/research support from: GSK provided belimumab for free for the Synbiose-2 clinical trial and provided an unrestricted grant to conduct the study.

Background:Systemic lupus erythematosus (SLE) is an autoimmune multisystemic disease with a wide variety of clinical manifestations, being one of them serositis, which includes pericarditis, pleuritis and peritonitis [1]. Incidence of serositis ranges between 11-54% [2].Objectives:To determine the prevalence of serositis in patients (pt) with SLE attended at the outpatient Lupus Unit and identify factors that could be used as predictors of this manifestation.Methods:Retrospective case-control study. 297 medical records of SLE pt were reviewed: 28 pt were diagnosed with serositis (cases) and were age- and sex-matched with 2 controls with SLE without serositis. Differences between cases and controls were analyzed as well as factors associated with serositis.Results:Patient’s characteristics are described in Table 1. The prevalence of serositis in our cohort was 9.42%. The difference between the prevalence of serositis in men and women was statistically higher in men, 30% vs 7.9% (p=0.001, CI 95%: 1.7%-42.4%). Serositis was diagnosed at an age of 41 ±14 years (y) and in 40.7% it was the first symptom. Time from SLE diagnosis to serositis was 4±5.3 y. 10 pt had recurrences: 6 had 2, and 4 had 3. Incidence of pericarditis and pleuritis was 78.6% and 82.1% respectively. 2 pt suffered from pericardial tamponade. Mean prednisone dose received during the serositis was 44.6±26.6mg. At the moment of serositis 100% were ANA+, 85.7% antidsDNA+, 80% CrithidiaDNA+, 57.9% antiRo60+, 52.6% antiRo52+, 15.9% antiLa+, 47.4% antiRNP+, 21.1% antiSm+, and 77.8% had low C3.When looking for serositis-associated factors we only found association with antidsDNA measured by Crithidia (p=0.016) and different measures of glucocorticosteroids (GC), having cases needed higher doses than controls (Table 1). Those with serositis had significantly received more mycophenolic acid (p=0.021) and marginally, more belimumab (p=0.056).Table 1.Comparison between groups of adverse maternal-fetal outcome.VARIABLESCASES (28)CONTROLS (54)p-value Female22 (33.3%)44 (66.7%)0.775 Male6 (37.5%)10 (62.5%) Caucasian20 (32.8%)41 (67.2%)0.693 Hispanic American7 (38.9%)11 (61.1%) Others1(33.3%)2 (66.6%)Arthritis22 (38.6%)35 (61.4%)0.219Leukopenia17 (34.0%)33 (66.0%)1.000Lymphopenia25 (33.8%)49 (66.2%)1.000Thrombocytopenia5 (20.8%)19 (79.2%)0.128Nephritis8 (50.0%)8 (50.0%)0.152Raynaud’s phenomenon6 (42.9%)8 (57.1%)0.263Haemolytic anaemia3 (42.9%)4 (57.1%)0.686Antinuclear antibodies28 (34.6%)53 (65.4%)1.000AntidsDNA23 (37.7%)38 (62.3%)0.295AntiSm9 (42.9%)12 (57.1%)0.425AntiRo5210 (41.7%)14 (58.3%)0.444AntiRo6013 (37.1%)22 (62.9%)0.645AntiRNP14 (43.8%)18 (56.3%)0.159CrithidiaDNA19 (47.5%)21 (52.5%)0.016Low C321 (39.6%)32 (60.4%)0.224Low C413 (38.2%)21 (61.8%)0.637Low CH5013 (39.4%)20 (60.6%)0.480SLICC*0.54 (±0.9)0.49 (±1.1)0.717SLEDAI*3.1 (±3.1)2.98 (±3.2) 0.844CorticosteroidsEver27 (38.6%)43 (61.4%)0,051Pulses ever9 (60.0%)6 (40.0%)0.033Maximum prednisone dose ever:18 (85.7%)3 (14.3%)0.00310-29mg14 (87.5%)2 (12.5%)30-60mg11 (45.8%)13 (54.2%)>60mg8 (47.1%)9 (52.9%)Conclusion:The prevalence of serositis was 9.42%. Serositis is significantly more frequent in SLE men than in women: almost ⅓ will develop serositis, so we need greater awareness of serositis in SLE men.CrithidiaDNA+ was identified as an associated factor of serositis. Furthermore, pt with serositis significantly received more pulses of GC and a higher maximum dose throughout the disease, which could imply a more aggressive form of SLE than in those without serositis. No correlation was found between serositis and any other characteristic.References:[1]Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725[2]Ryu S, Fu W, Petri MA: Associates and predictors of pleurisy or pericarditis in SLE. Lupus. Science. 2017, 4(1):e000221.Disclosure of Interests:None declared

Background:Belimumab (BEL), a monoclonal antibody that antagonizes B-lymphocyte stimulator, was first approved in 2011 for active, autoantibody-positive systemic lupus erythematosus (SLE). BEL has been studied for over 10 years; and while safety data from individual trials have been informative, a large integrated safety analysis has not yet been conducted.Objectives:Perform pooled analyses to evaluate the safety of BEL in adult patients with SLE.Methods:Aggregate analyses were performed using safety data for patients ≥18 years of age pooled from six randomised, placebo (PBO)-controlled BEL clinical trials (GSK studies: LBSL02, 110752, 110751, 112341, 113750, and 115471). Patients from GSK studies LBSL02, 110752, and 110751 received intravenous (IV) BEL 1, 4 (LBSL02 only), or 10 mg/kg, or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK studies 113750 and 115471 received IV BEL 10 mg/kg or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK study 112341 received subcutaneous (SC) BEL 200 mg, or PBO weekly. Safety analyses included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality of BEL (all doses and formulations combined) vs PBO at Week 52.Results:The pooled analysis included 4170 patients. Overall, 81.0% (n=2280/2815) of patients receiving BEL and 76.6% (n=1038/1355) of patients receiving PBO completed their respectively enrolled study; the most common reason for withdrawal was occurrence of an AE in both groups. The majority of patients were female (BEL: 94.5%; PBO: 93.6%), the mean age in both groups was 38 years, and baseline characteristics (race, SLE duration, disease activity, SLE damage, complement levels, anti-dsDNA binding, SLE medication usage) were similar between treatments.The incidence of patients experiencing ≥1 AE, ≥1 SAE, and mortality was similar across treatments (Table 1); the most commonly reported SAEs in both groups were infections and infestations (BEL: 5.4% [n=151/2815]; PBO: 5.9% [n=80/1355]). The mean duration of treatment exposure was similar between groups (BEL: 334.1 days; PBO: 325.3 days).A greater proportion of patients experienced AESI with BEL vs PBO for post-infusion/injection systemic reactions (from IV or SC administration) and depression/suicide/self-injury (Table 1). The proportion of patients experiencing an AESI of infections and malignancies was similar between groups.Conclusion:Consistent with individual studies, BEL demonstrated a similar safety profile to PBO in this large integrated safety analysis of six trials. These results support a positive benefit–risk profile of BEL in the treatment of adult SLE.Funding:GSKTable 1.Pooled AE dataN (%)PBO (IV + SC)N=1355BEL (IV + SC)N=2815AE1184 (87.4)2440 (86.7)SAE230 (17.0)421 (15.0)Severe AE (severe or life threatening)209 (15.4)377 (13.4)AE resulting in study drug discontinuation109 (8.0)184 (6.5)Death6 (0.4)16 (0.6)AESIPost-infusion/injection systemic reactions*110 (8.1)286 (10.2)Serious2 (0.1)13 (0.5)All infections of special interest (OIs, HZ, TB, sepsis)97 (7.2)173 (6.1)Serious17 (1.3)40 (1.4)All OIs92 (6.8)157 (5.6)Active TB5 (0.4)4 (0.1)All HZ59 (4.4)106 (3.8)All sepsis10 (0.7)20 (0.7)Malignancies excluding NMSC2 (0.1)8 (0.3)Including NMSC3 (0.2)12 (0.4)Depression (inc. mood disorders and anxiety)/suicide/self-injury92 (6.8)210 (7.5)Serious5 (0.4)9 (0.3)*Occurring on or within 3 days of infusion/injection date.HZ, herpes zoster; NMSC, non-melanoma skin cancer; OIs, opportunistic infections; TB, tuberculosisAcknowledgements:Medical writing assistance was provided by Helen Taylor, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Daniel J. Wallace Speakers bureau: GSK, Consultant of: GSK, Tatsuya Atsumi Speakers bureau: GSK, Consultant of: GSK, Grant/research support from: GSK, Mark Daniels Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Andreas Schwarting Speakers bureau: Novartis, Roche, GSK, Pfizer, Amgen, Consultant of: GSK, Grant/research support from: AbbVie, Pfizer, Novartis, GSK, Actelion, Fengchun Zhang: None declared, David Roth Shareholder of: GSK, Employee of: GSK

Background:Systemic Lupus Erythematosus (SLE) is a systemic immune complex (IC)-mediated disease associated with autoantibodies targeting multiple nuclear specificities (ANA). SLE has an aggressive nature among African populations. The role of SLE-related autoantibodies in the formation of IC has only been studied to a limited extent, and not at all in African SLE patients.Objectives:To quantify ANA specificities present in circulating IC in Sudanese and Swedish SLE sera and to compare to corresponding serum levelsMethods:93 Sudanese and 337 Swedish SLE patients who fulfilled the 1982 ACR classification criteria were included. IC were captured using magnetic microparticles coated with purified human C1q, then separated by a two-step elusion procedure (Figure 1). ANA-associated autoantibodies against dsDNA, Sm, the Sm/U1RNP complex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P antigen, proliferating cell nuclear antigen (PCNA) and histones were quantified in sera and corresponding IC using a bead-based multiplex immunoassay. The IC purification technique has been developed and validated in our laboratory (Sohrabian ARD 2018), and previously used to study treatment responses to belimumab in Swedish SLE patients (Sohrabian ART 2019). Occurrence of ANA specificities in serum was determined using manufacturer’s suggested cutoffs. These cutoffs were used in regression formulas to determine cutoffs for ANA levels detected in the corresponding IC.Results:Swedish patients had higher serum levels of anti-Sm, anti-dsDNA and anti-ribosomal P antibodies compared to Sudanese patients. On the contrary, IC levels of all ANA specificities except anti-SSA/Ro52 and anti-SSA/Ro60 were higher in Sudanese patients (Table 1 and Figure 2). Sudanese patients were more often positive for anti-Sm, anti- Sm/U1RNP, anti-dsDNA and anti-histone antibodies in IC, whereas a borderline statistical significance was found for only anti-Sm in corresponding serum samples (Table 1).Table 1.Levels median/meanSudanserumSweden serumPSudanICSwedenICPSSA/Ro5216/52.117/52.30.82.9/14.42.4/10.70.07SSA/Ro602.0/47.23.0/48.70.21.5/14.61.3/12.50.7SSB/La2.0/222.0/220.61.1/4.20.8/5.50.02Sm1.0/21.71.0/11.40.00080.5/4.20.3/1.3SmRNP1.0/20.51.0/160.23.7/8.62.0/4.6U1RNP6.0/43.87.0/40.20.91.0/3.50.6/2.20.0005dsDNA14.0/124.528.0/198.30.00132.1/50.812.4/25.4Ribosomal P1.0/9.32.0/11.70.00061.7/3.31.4/2.90.005Histone5.0/20.56.0/19.30.24.0/5.91.9/3.4PCNA5.0/8.45.0/8.90.611.1/14.27.0/11Occurrence n(%)serumserumPICICPSSA/Ro5230(32.2)105(31.7)0.918(19.3)55(16.6)0.5SSA/Ro6034(36.6)122(36.9)0.927(29)89(26.8)0.7SSB/La15(16.1)64(19.3)0.59(9.7)38(11.4)0.3Sm12(12.9)21(6.3)0.046(6.4)5(1.5)0.008SmRNP15(16.1)42(12.7)0.417(18.3)33(9.9)0.03U1RNP20(21.5)69(20.8)0.922(23.7)55(16.6)0.1dsDNA31(33.3)147(44.4)0.05564(68.8)105(31.6)Ribosomal P4(4.3)20(6)0.52(2.1)9(2.7)0.8Histone10(10.7)34(10.3)0.934(36.6)58(17.5)PCNA1(1.1)10(3)0.320(21.5)45(13.5)0.06Conclusion:ANA-associated autoantibodies are more accumulated in circulating IC from Sudanese than Swedish SLE patients. The clinical significance of these findings is yet to be investigated in our upcoming analysesDisclosure of Interests:None declared

ObjectivesTo investigate corticosteroid and opioid use among patients with SLE and to examine the impact of belimumab initiation on the use of other SLE therapies.MethodsWe identified adult patients with SLE (International Classification of Diseases, 9th Revision/10th Revision 710.0 and M32) between 1 January 2012 and 31 May 2018 (earliest SLE diagnosis=index date) within MarketScan administrative claims data. Patients were followed from index date for a minimum of 12 months and until the earlier of disenrolment in their health plan or study end (31 May 2018). Corticosteroid utilisation, corticosteroid dose (in prednisone equivalents) and opioid utilisation (overall, by strength (weak, strong) and by duration (chronic use defined as >90 days of cumulative drug supply)) were measured during follow-up. Oral corticosteroid and opioid use were compared in the 6 months before and after initiation of belimumab.ResultsThere were 49 413 patients with SLE eligible for analysis (mean (SD) age: 50.1 (14.0) years, 90.2% female). Of these, 68.5% received corticosteroids, and the average number of prescriptions was 4.59 (4.11) over the first 12 months of follow-up. Among patients with oral corticosteroids, average daily dose was 19.4 (14.2) mg and 59.6% had an average daily dose of ≥15 mg. Half (52.6%) had at least one opioid prescription and of these, 34.6% had chronic use over the first 12 months of follow-up. Among patients initiating belimumab during follow-up (n=1710), oral corticosteroid use decreased by 9.1% (p=0.001), and average daily dose decreased from 14.5 (18.4) mg to 11.9 (18.0) mg (pConclusionsA high proportion of patients with SLE are treated with corticosteroids to control SLE and opioid therapy to manage chronic pain. While there was no change in opioid use, oral corticosteroid use and dose intensity decreased following initiation of belimumab.

ObjectiveLong-term extension (LTE) studies of belimumab in SLE do not include a comparator arm, preventing comparisons between belimumab plus standard therapy and standard therapy alone for organ damage accrual. Propensity score matching can be used to match belimumab-treated patients from LTE studies with standard therapy–treated patients from observational cohort studies. This analysis was designed to compare organ damage progression between treatment groups (belimumab plus standard therapy vs standard therapy alone) in patients with SLE with ≥5 years of follow-up, reproducing our previous study with more generalisable data.MethodsThis exploratory post hoc analysis used a heterogeneous population of US and non-US patients receiving monthly intravenous belimumab from pooled BLISS LTE trials (BEL112234/NCT00712933) and standard therapy–treated patients from the Toronto Lupus Cohort. Sixteen clinical variables were selected to calculate the propensity score.ResultsThe 592 LTE and 381 Toronto Lupus Cohort patients were highly dissimilar across the 16 variables; an adequately balanced sample of 181 LTE and 181 matched Toronto Lupus Cohort patients (mean bias=3.7%) was created using propensity score matching. Belimumab treatment was associated with a smaller increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) over 5 years than standard therapy alone (mean treatment difference=–0.453 (95% CI –0.646 to –0.260); pConclusionUsing propensity score matching, this highly heterogeneous sample was sufficiently matched to the Toronto Lupus Cohort, suggesting that patients treated with intravenous belimumab may have reduced organ damage progression versus standard therapy alone. This analysis of a large and diverse pooled SLE population was consistent with our previously published US-focused study.

We read with interest the article by Chatzidionysiou et al ,1 which reported a post-hoc analysis of two trials on intravenous belimumab in systemic lupus erythematosus (SLE), showing a significant reduction of antiphospholipid antibodies (aPL) only in patients cotreated with antimalarials. However, this post-hoc analysis focused on anticardiolipin antibodies (aCL) only, with no data on anti-β2-glycoprotein I (antiβ2GPI) antibodies, which display the best diagnostic/prognostic value in antiphospholipid antibodies syndrome (APS). Moreover, although long-term use of antimalarials was reported to reduce aPL levels by itself,2 no information on the duration of antimalarials cotreatment was reported.1 Interestingly, treatment with belimumab was recently reported to induce aCL and antiβ2GPI disappearance in a small case series of patients with SLE-associated APS.3 We also reported a significant reduction in aCL and antiβ2GPI titres in 12 patients with SLE on belimumab, either alone or associated with antimalarials.4 This study aimed to assess the effect of subcutaneous belimumab (200 mg/week) versus placebo, in association with standard therapy +/- antimalarials, on aCL and antiβ2GPI titers in patients with SLE, …

We thank Dr Bettiol et al 1 for their interest in our article.2 Dr Bettiol et al performed a post-hoc analysis on a different randomised controlled trial of subcutaneous belimumab in systemic lupus erythematosus (SLE). The authors evaluated the effect of treatment with belimumab on the levels of anticardiolipin antibodies (aCL) (IgG, IgM and IgA) but also of anti-β2-glycoprotein I (antiβ2GPI) antibodies. The latter was unfortunately not available in BLISS-76 and BLISS-52 trials, as acknowledged in the limitations of our post-hoc analysis. The authors have also extended our observation about the effect of co-treatment with antimalarials on antiphospholipid antibody (aPL) titres in the belimumab versus the placebo group, by examining the duration of their use. We agree with the authors that the duration of antimalarials is of high clinical significance. In addition to previous retrospective studies,3 we have recently shown in …

Background:Systemic lupus erythematosus (SLE) is an autoimmune disorder more prevalent in the Asian population vs Caucasians. Belimumab (BEL), a monoclonal antibody targeting B-lymphocyte stimulator, is approved in patients (pts) ≥5 years with active, autoantibody-positive SLE.Objectives:Evaluate long-term safety and efficacy of intravenous (IV) BEL + standard SLE therapy (SST) in pts with SLE in Japan/Korea.Methods:In this Phase 3, multicentre, open-label (OL) study (BEL114333;NCT01597622), eligible (≥18 years of age) completers of the double-blind phase of GSK study BEL113750 in Japan and South Korea or the subcutaneous OL phase of GSK Study BEL112341 in Japan, received monthly BEL 10 mg/kg IV plus SST. Primary endpoints: safety assessments. Key secondary endpoints: SRI4 response rate at each scheduled visit (observed data), defined as a ≥4-point reduction from baseline in SELENA-SLEDAI score, no worsening in PGA (Results:Overall, 142 pts were enrolled (Japan n=72; Korea n=70), 104 (73.2%) completed the study, 1 (0.7%) died and 37 (26.1%) withdrew.Overall, 139 (97.9%) pts had ≥1 adverse event (AE) (Table). Most frequent AEs included: nasopharyngitis (60.6%); headache (28.2%); cough, herpes zoster and viral upper respiratory tract infection (18.3% each). Serious AEs (SAEs) occurred in 48 (33.8%) pts. Most common SAEs were infections and infestations, reported in 24 (16.9%) pts (Table). During this study, the annual incidence of AEs, including SAEs and AESI, remained stable or declined, with no trends of clinical concerns regarding the incidence of Grade 3 or 4 values for laboratory parameters. There was 1 transient positive immunogenicity result of no clinical concern.Table.The proportion of SRI4 responders was 47.8% at Year 1 (Week 24) and tended to increase numerically up to 84.6% at Year 7 (Week 48). The proportion of pts with a ≥4-point decrease from baseline in SELENA-SLEDAI score numerically increased from 51.5% at Year 1 (Week 24) to 84.6% at Year 7 (Week 48). Proportion of pts with no PGA worsening was 91.3-100% and the proportion with no new BILAG 1A/2B organ domain scores was 93.3-100% up to Year 7 (Week 48). A total of 21 (14.8%) pts had 24 severe SFI flares.Conclusion:BEL was well tolerated as add-on therapy to SST for ≤7 years in pts with SLE from Japan/Korea. Safety results were consistent with the known BEL safety profile.Study funding: GSK.Disclosure of Interests:Yoshiya Tanaka Grant/research support from: Received research grants from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono, Speakers bureau: Received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Sang-Cheol Bae: None declared, Damon Bass Shareholder of: GSK, Employee of: GSK, Myron Chu Shareholder of: GSK, Employee of: GSK, Paula Curtis Shareholder of: GSK, Employee of: GSK, Kathleen DeRose Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Regina Kurrasch Shareholder of: GSK, Employee of: GSK, Jenny Lowe Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Background:Systemic lupus erythematosus (SLE) is autoimmune connective tissue disorder of unclear etiology. It is characterized by autoantibody production and a variety of clinical manifestations. The introduction of biological treatment over the past few years provided an opportunity for a disease control.Objectives:The aim was to assess the effectiveness and safety profile of Belimumab in the treatment programs of SLE patients during a 2 year period.Methods:We initiated a prospective observational study of SLE patients in the Rheumatology Department in University Hospital St Marina – Bulgaria. The study comprises data from 26 patients at baseline before Belimumab treatment initiation and data after 6, 12, 18 and 24 months of treatment. All patients were with moderate disease activity according to SELENA – SLEDAI index and were on treatment with immunosuppressive drug (azathioprine) and glucocorticoids (GCs). We observed the change in the dosage of glucocorticoids over the observed period, the number of flares of SLE, as well the SELENA – SLEDAI index change. Safety profile of Belimumab was also registered.Results:We included 26 patients with SLE over a period of 4 years – between 2015 and 2019. The mean age was 45.8 + 11.4 years and 94% were Caucasian females. All patients were on a stable dosage of GCs at least 3 months before the first infusion of Belimumab and azathioprine 100 mg daily. Ninety percent of patients were diagnosed with SLE for more than 6 years according to ACR – SLE criteria. All of SLE patients were with moderate disease activity. Main reasons for biological treatment decision were persistent mucocutaneous manifestations (20%), polyarthritis (15%), haematological disturbances (35%) and persistent immunological markers (30%). One patient was excluded from the study due to infusion- related flush and severe hypotension reaction while the rest 25 completed the observation. We investigated and analyzed haematological results, ANA, anti – ds DNA, anti – Sm autoantibodies and complement fractions at baseline as well on the 12th and 24th month of treatment. The mean SELENA – SLEDAI index changed from 8.9 to 4.5 after 12 months of treatment and remained unchanged until the end of the study. We observed a mean reduction of GCs daily dosage from 12 mg to 6 mg after 18 months.Conclusion:Biological treatment with Belimumab added to the standard treatment with GCs and AZA in patients with non-lupus nephritis SLE patients adds additional benefits. Our results show that there is a reduction in SLEDAI index as well as reduction in daily GCs intake. Safety profile is not different from the one reported previously.Disclosure of Interests:None declared

Background:Belimumab (BEL) is the first treatment approved in children ≥5 years of age with cSLE. This recent approval was based on favourable results of the PLUTO trial, evaluating efficacy and safety of intravenous (IV) BEL, plus standard SLE therapy (SST), vs placebo (PBO), in children with cSLE.1Objectives:To evaluate the SLE Responder Index 4 (SRI4) sensitivity of response for the comparison of BEL vs PBO at Week (Wk) 52.Methods:In PLUTO (NCT01649765; GSK study BEL114055), an ongoing Phase 2, randomised, PBO-controlled, double-blind study, patients (pts) 5–17 years of age with active cSLE were randomised to monthly BEL 10 mg/kg IV, or PBO, plus SST, for 52 weeks. The primary efficacy endpoint was the SRI4 response rate at Wk 52. Pre-specified sensitivity analyses supporting the primary efficacy endpoint for the intention-to-treat (ITT) population included unadjusted, last observation carried forward (LOCF), completer responses, and response using SLE Disease Activity Index (SLEDAI) 2K proteinuria scoring rule (4-point score for proteinuria >0.5 g/24 h), all at Wk 52. Completers were pts who completed 52 weeks of treatment. Any pts who withdrew or received protocol-prohibited medication or a dose of allowable medication that resulted in treatment failure prior to the Wk 52 visit had missing data handled using LOCF (missing values imputed using the last previous non-missing value). Statistics are descriptive.Results:Overall, 93 pts were randomised (BEL, n=53; PBO, n=40). Majority (94.6%) of pts were female, mean (standard deviation [SD]) age was 14.0 (2.49) years and mean (SD) disease duration was 2.4 (1.93) years. By Wk 52, numerically more BEL (52.8%) than PBO (43.6%) pts were SRI4 responders; difference vs PBO 9.24; odds ratio (OR; 95% confidence interval [CI]) vs PBO 1.49 (0.64, 3.46). For each sensitivity analysis (unadjusted, LOCF, completer, and SLEDAI 2K responses) the odds of being a responder at Wk 52 were higher for pts receiving BEL vs PBO (Table).Table.Sensitivity analyses: SRI4 response at Wk 52PBO(n=40)BEL(n=53)Unadjusted response (ITT), n*3953 n (%)17 (43.6)28 (52.8) Observed difference vs PBO9.24 OR (95% CI)†vs PBO1.45 (0.63, 3.33)LOCF response (ITT), n*3953 n (%)18 (46.2)30 (56.6) Observed difference vs PBO10.45 OR (95% CI)‡vs PBO1.51 (0.65, 3.52)Completer response (completers), n*3045 n (%)17 (56.7)27 (60.0) Observed difference vs PBO3.33 OR (95% CI)‡vs PBO1.16 (0.44, 3.09)Response using SLEDAI 2K (ITT), n*3953 n (%)17 (43.6)28 (52.8) Observed difference vs PBO9.24 OR (95% CI)‡vs PBO1.49 (0.64, 3.46)*One pt was excluded because they did not have a baseline Safety of Estrogens in Lupus National Assessment (SELENA)-SLEDAI assessment;†calculated from a logistic regression model for the comparison between BEL and PBO without adjustment for any covariates;‡calculated from a logistic regression model for the comparison between BEL and PBO with covariates treatment group, baseline age (5–11 years vs 12–17 years), and baseline SELENA-SLEDAI score (≤12 vs ≥13)Conclusion:The results of the SRI4 primary efficacy endpoint sensitivity analyses further support a favourable effect for BEL vs PBO.References:[1]Brunner HI,et al.Arthritis Rheumatol.2018;70(59): 3224–5, Abst. 2867Acknowledgments:We acknowledge all PLUTO investigators (PRINTO, PRCSG and otherwise affiliated). Study funding: GSK.Disclosure of Interests:Nicolino Ruperto Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Eli-Lilly, EMD Serono, GSK, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi and Takeda, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis, Masaaki Mori Grant/research support from: Abbvie Japan, Asahikasei Pharmaceutical, Ayumi Pharmaceutical, CSL Behring, Chugai Pharmaceutical, Japan Blood Products Organization, MSD K.K., Nippon Kayaku, UCB Japan, Consultant of: Daiichi Sankyo, Taisho Pharmaceutical, Jacqueline Clinch Consultant of: Alexion, Speakers bureau: Alexion, Reema Syed: None declared, Naomi Iwata Speakers bureau: Sanofi K.K, Damon Bass Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Mohamed Okily Shareholder of: GSK, Employee of: GSK, Gina Eriksson Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK

Background:The whole management of systemic sclerosis (SSc) remains to be defined while trials mainly focus on the treatment of different organ involvement and disease-modifying treatments are still not available.Objectives:To assess the safety and efficacy of tofacitinib (TOF) treatment on skin and musculoskeletal involvement as compared to methotrexate (MTX) treatment in patients with early SSc.Methods:In this 52-week, prospective, investigator-initiated, open-label, single-centre study, 66 patients with SSc were enrolled. Thirty-three patients received 5mg of oral TOF twice a day; and thirty-three received 7.5-10 mg of MTX weekly. The primary outcome measures were: skin fibrosis improvement at week 26, assessed by the reduction in skin thickness - evaluated by the modified Rodnan skin score (mRSS) and the ultrasound (US) measured skin thickness; improvement in the musculoskeletal involvement, assessed by the reduction in the joint and tendon score (US10SSc score); and adverse events from baseline to week 26. The dynamics in the outcome measures within each group were examined through Wilcoxon tests and between-group comparisons were performed through Mann-Whitney U and Chi-square tests.Results:At baseline, both groups of patients had similar median scores with no significant differences on all measures: mRSS (p = 0.589), US measured skin thickness (p = 0.822), and US10SSc score (p = 0.918). At week 26, significant differences were observed between the two treatment groups as the TOF treated patients showed a greater reduction in mRSS and musculoskeletal manifestations. In the TOF group, the median mRSS score decreased by 50% from 24 to 12 (IQR = 7.50) versus a smaller decrease of 8.70% in the MTX group, from 23 to 21 (IQR = 8.00), p < 0.001. The median US measured skin thickness in the TOF treated patients decreased by 12.87% from 1.71 to 1.49 (IQR =0.31) versus a decrease of 4.73%, from 1.69 to 1.61 (IQR =0.52) in the MTX group, p = 0.040. The US10SSc median score in the TOF group decreased by 56.25% from 16 to 7 (IQR = 6.50) versus a decrease of 12.5% in MTX group from 16 to 14 (IQR =10.50), p < 0.001. There was no significant difference between the groups in the number of adverse events from baseline to week 26. No cases of herpes zoster and deep vein thrombosis were observed in the TOF group.Conclusion:The data show that in early SSc TOF may lead to a significant improvement of skin thickness, measured with the mRSS and US, and of the musculoskeletal involvement, measured by the US10SSc score. TOF has also shown a satisfactory safety profile.References:[1]Elhai M, Boubaya M, Distler O, et al. Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis. 2019 Jul;78(7):979-987.[2]Khanna D, Denton CP, Lin CJF, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018;77:212-220.[3]Gordon JK, Martyanov V, Franks JM, et al. Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. Arthritis Rheumatol. 2018 Feb;70(2):308-316.Figure 1.Panel A - Dynamics in mRSS between baseline and week 26 in the MTX group;Panel B- Dynamics in mRSS between baseline and week 26 in the TOF group.Figure 2.Panel A - Dynamics in skin thickness between baseline and week 26 in the MTX group; Panel B - Dynamics in skin thickness between baseline and week 26 in the TOF group.Disclosure of Interests:Rositsa Karalilova: None declared, Tanya Sapundzhieva: None declared, Zguro Batalov: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim, Anastas Batalov: None declared

Background:BAFF and APRIL are TNF superfamily members that bind both TACI and BCMA on B cells; BAFF also binds BAFF-R. Together, BAFF and APRIL support B cell development, differentiation, and survival. Their co-neutralization dramatically reduces B cell function, including antibody production, whereas inhibition of either BAFF or APRIL alone mediates relatively modest effects.Objectives:While CTLA-4-based therapeutics that block T cell costimulation provide safe and moderately effective T cell inhibition in many disease settings, and while B cell targeting therapies have demonstrated promising therapeutic potential, we postulate that improved, combined BAFF and APRIL inhibition, either alone or coupled with inhibition of T cell costimulation, will provide more effective and durable relief from severe B cell-related autoimmune diseases like SLE.Methods:We used our directed evolution platform to identify variant domains of the TNF family receptors TACI or BCMA that exhibit enhanced affinity for BAFF and APRIL as compared to their wild-type (WT) counterparts. These variant TACI or BCMA domains (vTD), alone or together with platform-derived CTLA-4 domains (vIgD), were fused to a modified human IgG1 Fc lacking effector function, yielding a panel of immunomodulatory molecules: TACI vTD-Fc, BCMA vTD-Fc, TACI vTD/CTLA-4 vIgD-Fc, & BCMA vTD/CTLA-4 vIgD-Fc. All were evaluated for functional activity: 1)in vitroin primary human B cell & MLR assays and in a Jurkat/NF-kB reporter cell line expressing TACI, and 2)in vivoin standard immunization models, and in the bm12-induced and NZB/NZW spontaneous mouse models of lupus.Results:The novel engineered TACI vTD-Fc or BCMA vTD-Fc fusion proteins significantly inhibited BAFF- and APRIL-mediated signalingin vitroin TACI+Jurkat cells. TACI (or BCMA) vTD/CTLA-4 vIgD-Fc proteins also attenuated T cell activation in primary human lymphocyte assays. When administered to mice, these molecules rapidly and potently reduced key B and T cell subsets, including plasma cells, follicular T helper cells, germinal center cells, & memory T cells. Treatment with TACI vTD-Fc or TACI vTD/CTLA-4 vIgD-Fc proteins also significantly reduced titers of antigen-specific antibodies in immunized mice more so than abatacept or WT TACI-Fc, and potently suppressed anti-dsDNA autoantibodies, blood urea nitrogen levels, proteinuria, and renal immune complex deposition in the bm12 & NZB/W lupus models.Conclusion:Directed evolution of TNFR and IgSF domains has successfully facilitated the development of Fc fusion proteins containing TACI or BCMA vTDs, with or without fusion to CTLA-4 vIgDs. These novel immunomodulators consistently demonstrate potent immunosuppressive activity and efficacyin vitroandin vivo, appearing superior to existing and/or approved immunomodulators like belimumab, abatacept, or atacicept. Such biologics may therefore be attractive candidates for the treatment of serious autoimmune diseases, particularly B cell-related diseases such as SLE, Sjogren’s syndrome, etc.Disclosure of Interests: :Stacey R. Dillon Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Lawrence S. Evans Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Mark W. Rixon Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Joe Kuijper Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Dan Demonte Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Katherine E. Lewis Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Steve Levin Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Kayla Kleist Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Sherri Mudri Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Susan Bort Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Janhavi Bhandari Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Fariha Ahmed-Qadri Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Jing Yang Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Michelle A. Seaberg Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Rachel Wang Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Russell Sanderson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Martin F. Wolfson Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc., Jan Hillson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Stanford L. Peng Shareholder of: Alpine Immune Sciences, Inc., Employee of: CMO and President of Alpine Immune Sciences, Inc., Kristine M. Swiderek Shareholder of: Shareholder of Alpine Immune Sciences, Inc., Employee of: Employee of Alpine Immune Sciences, Inc.

Background:SLE is managed by variable combinations of five drug classes: antimalarials, biologics, corticosteroids, non-steroidal anti-inflammatory agents, and immunosuppressants. Opioids are commonly prescribed to SLE patients despite not being effective for the management of long-term musculoskeletal pain.1Objectives:To describe corticosteroid and opioid use among SLE patients in the United States, and the impact of belimumab initiation on prescribing patterns.Methods:This retrospective study used MarketScan administrative claims databases to select insured adults, age ≥18, with a diagnosis (ICD-9/10 710.0 & M32) of SLE between 1/1/2012 and 5/31/2018 (earliest SLE diagnosis = index date). Patients were followed from index through the earliest of health plan disenrollment or 5/31/2019 (minimum of 12 months). Corticosteroid use was measured in the 12 months following SLE index date. Average daily dose of oral corticosteroids in prednisone equivalents was measured for 12 months after corticosteroid initiation. Opioid use was measured overall, and by strength and length of treatment (chronic use defined as >90 days of supply). Oral corticosteroid and opioid use were compared in the 6 months before and after initiation of belimumab.Results:Of 49,413 SLE patients eligible for analysis, mean [SD] age was 50.1 [14.0] years, 90.2% were female, and average follow-up was 3.6 [1.9] years. 89.8% of patients received any SLE treatment and 68.5% received corticosteroids. The average number of corticosteroid prescriptions was 4.6 [4.1] during 12 months of follow-up. 52.6% of patients had ≥1 claim for an opioid prescription in the 12 months after SLE index and 34.6% were identified as having chronic opioid treatment. Among patients with oral corticosteroid treatment and 12 months of study enrollment post-corticosteroid initiation, the average daily dose for oral corticosteroids was 19.4 [14.2] mg and 59.6% had a high average daily dose of >15mg (Figure 1). Among 1,710 patients with belimumab treatment and 6 months of study enrollment after the first prescription, use of oral corticosteroids decreased by 9.1% (p=0.001), average daily dose decreased from 14.5 [18.4] mg to 11.9 [18.0] mg (pTable 1.Before BelimumabAfter Belimumabp-value, pre vs.(N =1,710)(N =1,710)post BelimumabPatients with an oral steroid prescription (N, %)1,24272.6%1,08663.5%0.001Number of prescriptions (Mean, SD)2.32.32.12.3Average daily dose (Mean, SD)14.518.411.918.0Low average daily dose (>0 to 21012.3%25514.9%0.037Medium average daily dose (7.5 - 38922.7%33419.5%0.041High average daily dose (15 mg or more) (N, %)64337.6%49729.1%Patients with an opioid prescription (N, %)90152.7%86150.4%0.341Weak opioids35620.8%31218.2%0.089Strong opioids69940.9%69540.6%0.915Acute Opioid Use53859.7%48656.4%0.165Chronic opioid use36340.3%37543.6%0.165Conclusion:These results suggest that a strikingly high proportion of patients with SLE are treated with corticosteroids to control the disease and opioid therapy to manage chronic pain. While there was no change in opioid use, corticosteroid use decreased following initiation of belimumab.References:[1]Chen SK, Feldman CH, Brill G, et al. Use of prescription opioids among patients with rheumatic diseases compared to patients with hypertension in the USA: a retrospective cohort study. BMJ 2019;9:e027495Disclosure of Interests: :Julie Birt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jianmin Wu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kirstin Griffing Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Natalia Bello Vega Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Nicole Princic Employee of: I work for IBM Watson Health who was paid by Eli Lilly who funded this research., Isabelle Winer Employee of: I work for IBM Watson Health who was paid by Eli Lilly who funded this research., Carolyn Lew Employee of: I work for IBM Watson Health who was paid by Eli Lilly who funded this research., Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca

Background:Belimumab (BEL) is a human monoclonal antibody that specifically inhibits B-cell activating factor (BAFF). PLUTO is an ongoing trial evaluating efficacy and safety of intravenous (IV) BEL in children ≥5 years of age with cSLE. Efficacy, and safety endpoints of PLUTO have been reported;1briefly, numerically more BEL vs PBO pts met the primary and major secondary efficacy endpoints. We present patient (pt) response to BEL over time.Objectives:To evaluate changes in SLE Responder Index (SRI) 4 and SRI6 responses, and disease activity over 52 weeks, in paediatric pts receiving BEL, or placebo (PBO), plus standard SLE therapy (SST).Methods:PLUTO (GSK Study BEL114055,NCT01649765) is a Phase 2, randomised, double-blind, placebo-controlled study. Pts 5–17 years of age with active cSLE were randomised to monthly BEL 10 mg/kg IV, or PBO, plus SST. Endpoints assessed: SRI4 and SRI6 response rate, mean percentage and absolute change from baseline in Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLE Disease Activity Index (SLEDAI) and Physicians’ Global Assessment (PGA) scores, and percentage of pts with no new British Isles Lupus Assessment Group (BILAG) 1A/2B organ domain scores compared with baseline, all by study visit. The last-observation-carried-forward (LOCF) principle (missing values imputed using the last available non-missing value) was applied to pts who withdrew or received protocol-prohibited medication or a dose of allowable medication that resulted in treatment failure prior to the Week (Wk) 52 visit. Descriptive statistics were used.Results:A total of 93 pts (94.6% female, mean [SD] age 14.0 [2.49] years) were randomised for the intention-to-treat (ITT) population: 53 to BEL and 40 to PBO. Mean (SD) BEL and PBO baseline scores were 10.3 (3.34) and 10.4 (3.63) for SELENA-SLEDAI and 1.3 (0.43) and 1.4 (0.42) for PGA, respectively. Pt number with at least BILAG 1A/2B organ domain involvement at baseline was 37 (69.8%) for BEL and 29 (72.5%) for PBO. SRI4 and SRI6 responses over 52 weeks were mostly numerically higher with BEL than PBO; more BEL than PBO pts were SRI4 and SRI6 responders at Wk 52 (Figure 1). Unadjusted mean (SE) percentage changes from baseline over time in SELENA-SLEDAI and PGA scores generally favoured BEL over PBO, as did unadjusted mean (SE) absolute changes (Figure 2). Wk 52 adjusted mean (95% CI) percentage treatment difference vs PBO was -4.0% (-21.8, 13.9) for SELENA-SLEDAI and -6.1% (-23.9, 11.7) for PGA, while Wk 52 adjusted mean (95% CI) treatment difference vs PBO was -0.7 (-2.4, 1.1) for SELENA-SLEDAI and -0.1 (-0.3, 0.1) for PGA. Over the study duration, numerically more BEL than PBO pts had no new BILAG 1A/2B organ domain scores (Figure 2).Figure 1.SRI4 and SRI6 response by study visitFigure 2.SELENA-SLEDAI and PGA score mean percentage and absolute change from baseline, and no new BILAG 1A/2B organ domain scores compared with baseline, all by study visitConclusion:In line with the main analyses performed at Wk 52,1further analyses of responses over time in SRI4, SRI6 and disease activity generally favoured BEL over PBO. Combined, these results continue to support the efficacy profile of IV BEL in the treatment of children with cSLE.References:[1]Brunner HI,et al.Arthritis Rheumatol.2018;70(59): 3224–5, Abst. 2867Acknowledgments:We acknowledge all PLUTO investigators (PRINTO, PRCSG and otherwise affiliated). Study funding: GSK.Disclosure of Interests:Nicolino Ruperto Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Eli-Lilly, EMD Serono, GSK, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi and Takeda, Liza McCann: None declared, Syuji Takei Grant/research support from: Eisai, Consultant of: Novartis, Bristol-Myers Squibb, Speakers bureau: GSK, Sanofi, Tanabe-Mitsubishi, Novartis, Chugai, Ono, Abbvie, Eli-Lilly, Bristol-Myers Squibb, Clarissa Pilkington: None declared, Damon Bass Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Mohamed Okily Shareholder of: GSK, Employee of: GSK, Gina Eriksson Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis

Background:Lupus nephritis (LN), a serious manifestation of systemic lupus erythematosus (SLE), affects nearly 70% of patients (pts) in high-risk groups. To preserve renal function, LN requires fast and effective treatment. Despite medical advances, progression rates at 15 years to end-stage renal disease (ESRD) remain >40% for pts with diffuse proliferative LN. Belimumab (BEL), approved in pts aged ≥5 years with active SLE, improved renal parameters in pts with baseline renal involvement in apost hocanalysis of Phase 3 trials data.Objectives:To assess efficacy and safety of intravenous (IV) BEL vs placebo (PBO), plus standard therapy (ST), in pts with active LN.Methods:BLISS-LN is a Phase 3, randomised, double-blind, PBO-controlled, 104-week study (GSK Study BEL114054,NCT01639339). Adults with SLE and biopsy-proven LN (class III, IV, and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Primary endpoint: Primary Efficacy Renal Response (PERR); defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] within 20% of the pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: Complete Renal Response (CRR; defined as uPCR 2; no rescue therapy) at Wk 104; PERR at Wk 52; time to renal-related event (defined as ESRD/doubling of serum creatinine/renal worsening/renal disease-related treatment failure) or death. Other endpoints: time to PERR/CRR sustained through Wk 104; SLEDAI-S2K score Results:Overall, 448 pts were randomised (efficacy: 223/group; safety: 224/group). Significantly more BEL (43%) than PBO (32.3%) pts achieved PERR at Wk 104 (OR 1.55, 95% CI 1.04, 2.32; p=0.0311). More BEL than PBO pts achieved key secondary and other efficacy endpoints (Table).Overall, 214 (95.5%) BEL and 211 (94.2%) PBO pts had ≥1 adverse event (AE); 58 (25.9%) BEL and 67 (29.9%) PBO pts had ≥1 serious AE; 29 (12.9%) pts in each group had ≥1 AE resulting in study treatment discontinuation; 4 (1.8%) BEL and 3 (1.3%) PBO pts developed on-treatment fatal AEs.Conclusion:In the largest LN study to date, data from BLISS-LN demonstrate that BEL plus ST significantly improves LN renal responses compared with ST alone with a favourable safety profile.Study funding: GSK.Table.Endpoint, n (%)PBO(n=223)BEL(n=223)OR/HR (95% CI) vs PBOp-valueCRR at Wk 104*44 (19.7)67 (30.0)OR 1.74(1.11, 2.74)0.0167PERR at Wk 52*79 (35.4)104 (46.6)OR 1.59(1.06, 2.38)0.0245Time to PERR throughWk 104†72 (32.3)96 (43.0)HR 1.46(1.07, 1.98)0.0157Time to CRR throughWk 104†44 (19.7)67 (30.0)HR 1.58(1.08, 2.31)0.0189Time to renal-related event or death†63 (28.3)35 (15.7)HR 0.51(0.34, 0.77)0.0014SLEDAI-S2K score 41 (18.4)62 (27.8)OR 1.76(1.11, 2.78)0.0164*PBO and BEL columns represent the n (%) responders†Data presented as n (cumulative incidence)Disclosure of Interests:Richard Furie Grant/research support from: GSK, Consultant of: GSK, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Frederic Houssiau Grant/research support from: UCB, Consultant of: GSK, Zahir Amoura Grant/research support from: GSK, Roche, Consultant of: GSK, Astra Zeneca, Amgen, Mittermayer Santiago: None declared, Gabriel Contreras Grant/research support from: Genentech, Merck, Consultant of: Genentech, Merck, Ana Malvar Consultant of: GSK and Roche, chi chiu mok: None declared, Amit Saxena Consultant of: GSK, AZ, BMS, Xueqing Yu: None declared, Y.K. Onno Teng Grant/research support from: GSK, Consultant of: GSK, Aurinia Pharmaceuticals, Novartis, Carly Barnett Shareholder of: GSK, Employee of: GSK, Susan Burriss Shareholder of: GSK, Employee of: GSK, Yulia Green Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Christi Kleoudis Shareholder of: GSK, Consultant of: GSK, Employee of: Parexel, David Roth Shareholder of: GSK, Employee of: GSK

Background:Vaccination with 23-valent polysaccharide pneumococcal vaccine (PPV-23) in systemic lupus erythematosus (SLE) provides the prevention of severe respiratory infections in patients receiving immunosuppressive therapy. The importance of this vaccination significantly increases before and during treatment with biologics.Objectives:The aim of the study was to evaluate the immunogenicity of PPV-23 in SLE patients.Methods:The study included 52 patients with SLE, including 44 women and 8 men, aged 19 to 68 years. The duration of the disease varied from 9 months to 39 years. At the time of vaccination 7 patients had high, 10 – moderate, 30 – low activity of the disease according to SLEDAI 2K, and 5 had remission. 50 patients received glucocorticoids (GC) 5-30 mg/day equivalent to prednisone, 39 – hydroxychloroquine (GCH), 29 – cytostatics (CS), 20 – biologics: 10 – rituximab (RTM), 10 – belimumab (BLM). 1 dose (0.5 ml) of PPV23 was administered subcutaneously. During the visits, standard clinical and laboratory tests were performed, and the level of antibodies (Ab) to S.pneumoniae in blood serum was determined (VaccZymeTMPCPIg 2 kits – The Binding Site Ltd, Birmingham, UK).Results:In 1-2 months after the vaccination 78.7% of patients had a significant (more than 2 times compared to baseline) increase in the concentration of Ab to the pneumococcal cell wall polysaccharides. A year after vaccination, 61.5% of patients (“responders”) had a significant increase in the concentration of anti-pneumococcal Ab. 20 (38.5%) of 52 patients were considered “non-responders”. Median concentration of anti-pneumococcal Ab was 67[42.6; 105.8] mg/l at visit 1 (initially), 405[143.5; 468.4] mg/l at visit 2 (in 1-2 months), 166.9[77.5; 377.4] mg/l at visit 3 (in 12 months).There were clear differences in the degree of the vaccinal response depending on the therapy: in 20 patients receiving biologics full vaccinal response was achieved significantly less frequently than in patients who did not receive these drugs (40% and 75%, respectively), p=0.02. There were no obvious differences in the vaccinal response during treatment with RTM and BLM (40% of responders in both groups). The vaccinal response significantly decreased during treatment with biologics in combination with GC+/ - GCH (50% of responders). The lowest vaccinal response was observed in patients receiving biologics in combination with GC and CS + / - GCH (33.3% of responders).The analysis of the degree of the vaccinal response depending on the timing of vaccination and the time of biologics infusion was carried out. In the first group (n=6), vaccination was carried out at the optimal time in accordance with the recommendations of EULAR (2020). In the second group (n=14) vaccination was carried out in suboptimal time: during regular treatment with BLM (n=6), 1 week before the next introduction of RTM (n=2), 3-5 months after the last introduction of RTM (5), 1 week before the next introduction of RTM (n=1), 20 days after the BLM termination (n=1). In the first group with optimal vaccination terms, the number of responders was 66.7%, in the second group with suboptimal terms – 28.6%, p=0.27.Conclusion:Sufficient immunogenicity of PPV-23 was shown in SLE patients receiving immunosuppressive therapy. The negative impact of biologics on the vaccinal response was confirmed, especially if the vaccination was not performed at the optimal time in relation to the infusion of the drug or during monthly administration of BLM. If optimal vaccination terms are maintained during the treatment with or initiation of biologics (6 months after the last administration of RTM and 1 month before the next (or first) administration of RTM, 4 months after the last and 1 month before the next (or first) administration of BLM), the number of responders increases significantly. The lowest vaccinal response was obtained in patients receiving combined immunosuppressive therapy with biologics + GC+CS.Disclosure of Interests:None declared

We thank Mousavi et al for their interest in our study.1 2 Mousavi et al regret that we did not take into account different factors determined in the literature to be associated with increased risk of flare of the disease, such as ‘African American ethnicity’, disease onset ≤25 years and B Lymphocyte Stimulator (BLyS) serum levels ≥2 ng/mL.3 However, the studies cited by Mousavi et al included active patients with systemic lupus erythematosus (SLE) (eg, with a Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥6 for the Study of Belimumab in Subjects With Systemic Lupus Erythematosus (BLISS)-52 and BLISS-76 trials4), while in the CORTICOLUP study only clinically quiescent patients were included. The predictors of relapse are certainly not the same as for active or clinically quiescent …

ObjectiveTo examine the effects of belimumab initiation on healthcare resource utilisation (HCRU) and costs in SLE.MethodsThis retrospective observational cohort study used healthcare administrative claims data from the IBM MarketScan Commercial Claims and Encounters Database to identify patients with SLE billing codes who received ≥1 intravenous belimumab infusion between March 2011 and December 2015. The first belimumab administration was the ‘index date’. During the 6-month postindex period, nine belimumab infusions were recommended: three during the initiation period and six during the maintenance period. HCRU and cost data for inpatient admissions, emergency department visits, physician office visits, hospital-based outpatient visits, laboratory services, other outpatient services and outpatient pharmacy prescriptions were compared in the 6-month pre/postindex periods.ResultsOf the 1879 patients with SLE included, 43% received ≥3 intravenous initiation administrations. An average of 5.3 (SD: 2.4) of the nine recommended belimumab administrations were received within 6 months. In the 6-month preindex versus postindex periods, significant reductions were noted for inpatient hospitalisations (18% vs 9%, pConclusionsIn this study of real-world intravenous belimumab for SLE, adherence to recommended infusion schedules was low. Outpatient healthcare and associated costs were higher in the 6 months after belimumab was initiated, although inpatient costs were lower. Reasons for non-adherence with belimumab and implications should be investigated.

Post hoc analyses of the phase III trials of belimumab BLISS-521 and BLISS-762 revealed superiority of belimumab over placebo in patients with systemic lupus erythematosus (SLE) with high baseline disease activity, positive anti–double-stranded (ds)DNA titres and low complement levels, as well as in patients receiving corticosteroids.3 Later, real-life observations demonstrated that established organ damage prior to treatment initiation predicted reduced belimumab efficacy.4 We aimed at validating this finding in the BLISS-52 and BLISS-76 SLE populations. Access to data was granted by GlaxoSmithKline (Uxbridge, UK). In total, 1684 patients were included in the analysis. The BLISS-52 trial comprised 865 and the BLISS-76 trial 819 patients with SLE who were randomised to receive belimumab 1 mg/kg, belimumab 10 mg/kg or placebo, along with standard-of-care treatment. Organ damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).5 Response to treatment was defined as fulfilment of the SLE responder index 4 (SRI-4) conditions at week 52 (primary endpoint of the BLISS trials).1 2 Patients who withdrew or required changes in the background therapy other than those permitted by protocol …

In ARD , a group of outstanding investigators report the results of another lupus trial missing its primary endpoint, namely the Phase III CHABLIS-SC study aimed at testing the efficacy of blisibimod,1 composed of a tetrameric BAFF/BLyS domain fused to a human IgG1 Fc region. Interestingly, blisibimod displayed unequivocal effects on biomarkers, such as reduction of circulating B cells, serum immunoglobulin titres or anti-DNA antibodies and increase in complement levels, changes in line with its mode of action and known to correlate with improved clinical outcome. Moreover, although the trial was not intended to demonstrate renal efficacy, an interesting reduction of proteinuria was noticed. This paradox raises the possibility that the failure of CHABLIS-SC stems more from the choice of the primary efficacy endpoint than from the drug itself, the more so as BAFF/BLyS was proven to be an appropriate target in four previous clinical trials, namely the belimumab BLISS-52,2 BLISS-763 and BLISS-SC4 and the tabalumab ILLUMINATE-25 studies, all showing the same effects on biomarkers and a significant, although modest, clinical efficacy. Of note, while the primary outcome (SRI-6) failed in the CHABLIS-SC trial, a trend (p=0.056) in favour of blisibimod was demonstrated when a modified endpoint was used, which takes into account, besides SRI-6, achievement of a steroid dose reduction between weeks 40 and 52 compared with day 1. The main goal of this editorial is to propose a ‘U loop’ in …

Apart from animal studies,1 no human studies exist to document the transfer of belimumab (BEL) to the fetus and immunological alterations caused in the neonate.2 We report the case of a mother treated with BEL for systemic lupus erythematosus (SLE) both before and during pregnancy and present the immunological changes observed in the child at birth and during 7 months of follow-up. A 29-year-old woman with SLE from 2005 with arthritis and lupus skin disease. During her first pregnancy in 2005–2006, she had a severe flare of lupus with pericarditis and glomerulonephritis, hypertension and premature delivery at week 33. She recovered under therapy with prednisone, azathioprine (AZA; started after a normal thiopurine S-methyltransferase (TPMT) gen test) and hydroxychloroquine (HCQ), and experienced no relapse of lupus nephritis under continued triple therapy. In 2013, she developed severe lupus skin disease …

We thank Sbeih et al for their interest in our work. In their correspondence, they show longer time taken to achieve the Lupus Low Disease Activity State (LLDAS) and ‘remission’ than the Systemic Lupus Erythematosus Responder Index-4 (SRI-4) endpoint in a case series of 50 patients with SLE and active disease treated with intravenous belimumab 10 mg/kg.1 Sbeih et al state that the analyses we undertook in the study by Oon et al ,2 which was a post hoc evaluation of BLISS-52 and BLISS-76 trials for the LLDAS endpoint, ‘lack data on the time needed to achieve LLDAS…’. However, this is not correct. In supplementary figure 1A) of the publication by Oon et al …

We read with much interest the contribution of Oon et al 1 that was published recently in Annals of the Rheumatic Diseases, describing attainment of the lupus low-disease activity state (LLDAS) in a post-hoc analysis of the BLISS trials. At week 52, LLDAS was reached by 12.5% and 14.4% of patients treated with belimumab 10 mg/kg in BLISS-52 and BLISS-76, respectively. The authors conclude that LLDAS is a potential response indicator for future systemic lupus erythematosus (SLE) trials. As opposed to SLE responder index 4 (SRI4),2 which represents a change from baseline activity, LLDAS3 and remission4 are clinical states that should be targeted as they are associated with damage accrual reduction and include the notion of a low prednisone dose.5 Yet, these indicators should be further studied before being introduced into clinical trials. In particular, Oon et al ’s study lacks data on the time needed to achieve LLDAS and the clinical factors influencing its achievement. It is also important to consider the absence of relapse after an improvement of the disease. In this letter, we wish to provide additional data on the time needed, the probability of and the clinical predictors for achieving stable (ie, without subsequent relapse until month 12) LLDAS and remission state under belimumab. We included all patient with SLE treated with belimumab (intravenous 10 mg/kg on day 0, 14, 28 and then every 28 days) in our centre from March 2013 to May 2018 for an active disease despite standard therapy. Follow-up was …

Increased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjögren's syndrome (pSS).To evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS.Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjögren's syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in ≥30% in dryness score on a visual analogue scale (VAS), ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or25% improvement in any B cell activation biomarker values.Among 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjögren's Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmer's test did not change.These encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

We want to thank Dr Morton Scheinberg for his interest1 in our recent lupus guidelines communication.2 In his letter, he points out several concerns regarding belimumab which we had recommended at the same therapeutic level as other immunosuppressants for joint and skin manifestations. Few clarifications are needed. The development of our guidelines followed a rigorous methodology in which the evidence on effect estimates should come, when available, from randomised controlled trials (RCTs). We did not identify any clinical trial comparing belimumab against other immunosuppressants. Therefore, in considering this comparison, the development group had to rely on indirect evidence (the difference in belimumab effect against placebo and other immunosuppressants against placebo) or high risk of bias evidence (from observational studies). In this context, the panel agreed that the certainty that belimumab was better (or worse) than other immunosuppressants was low/very low and therefore decided not to recommend one over the others...

The paper on the First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus (SLE) points to some conclusions that need to be further clarified since the bulk of evidence points to a different direction.1 Belimumab safety and efficacy has been well documented since its approval during the last 5 years, and in particular the skin and joint domains appear to have …

BAFF/BLyS, a pivotal cytokine in B-cell development, survival and proliferation,1 became a trusted target in systemic lupus erythematosus (SLE) more than 15 years ago when the growth factor was shown to be involved in the pathogenesis of both preclinical models and human SLE.2 ,3 Anti-BLyS monoclonal antibody belimumab (BEL) was licensed in 2011 for the treatment of SLE based on the results of the BLISS 52 and 76 phase III trials, which showed superiority compared with placebo, based on the percentage of patients achieving the SLE Responder Index 4 (SRI-4), a composite endpoint requiring (a) a reduction of ≥4 points in SELENA-SLEDAI score, (b) no new British Isles Lupus Assessment Group 2004 (BILAG) index score A or no more than 1 new BILAG B score and (c) no worsening (increase ≥0.3 points from baseline) in Physician's Global Assessment. At week 52, the delta efficacy between BEL and placebo (both on top of standard of care) was 14.0% and 9.7% in favour of the study drug in BLISS 52 and 76, respectively.4 ,5 …