Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

Systemic lupus erythematosus.

The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions. In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

https://ard.bmj.com/content/annrheumdis/77/2/175.full.pdf

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

Objective
To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE).

Methods
Patients with moderate-to-severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results.

Results
Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA–SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25–2.25]; P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35–0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40–52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95–2.84]; P = 0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by ≥2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo.

Conclusion
In patients with moderate-to-severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.40049

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

Summary Background Type I interferons are involved in systemic lupus erythematosus (SLE) pathogenesis. In a phase 2 trial, anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1, suppressed interferon gene signatures and substantially reduced SLE disease activity. Here, we sought to confirm the efficacy of anifrolumab versus placebo in a phase 3 trial of adult patients with SLE and moderate-to-severe disease activity despite standard-of-care treatment. Methods TULIP-1 was a double-blind, randomised, controlled, phase 3 trial done at 123 sites in 18 countries. Included patients were aged 18–70 years, with moderate-to-severe SLE, and ongoing stable treatment with either prednisone or equivalent, an antimalarial, azathioprine, mizoribine, mycophenolate mofetil or mycophenolic acid, or methotrexate. Patients were randomly assigned (2:1:2) to receive placebo, anifrolumab 150 mg, or anifrolumab 300 mg intravenously every 4 weeks for 48 weeks. Stable standard-of-care treatment continued except for mandatory attempts at oral corticosteroid tapering for patients receiving prednisone or equivalent of 10 mg/day or more at baseline. The primary outcome was the difference between the proportion of patients who achieved an SLE responder index-4 (SRI-4) response at week 52 with anifrolumab 300 mg versus with placebo. Key secondary outcomes were the difference between the anifrolumab 300 mg group and the placebo group in: proportion of patients in the interferon gene signature test—high subgroup who achieved SRI-4 at week 52; proportion of patients on 10 mg/day or more corticosteroids at baseline who achieved a sustained dose reduction to 7·5 mg/day or less from week 40 to 52; proportion of patients with a cutaneous lupus erythematosus disease area and severity index (CLASI) activity score of 10 or higher at baseline who achieved a 50% or more reduction in CLASI score by week 12; proportion of patients who achieved SRI-4 at week 24; and annualised flare rate through week 52. Other measures of disease activity were also assessed at week 52, including the British Isles Lupus Assessment Group-based composite lupus assessment (BICLA). Safety was also assessed. Efficacy and safety analyses were done in the population of patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT02446912). Findings Between June 9, 2015, and June 16, 2017, 457 patients were randomly assigned to the anifrolumab 300 mg group (n=180), the anifrolumab 150 mg group (n=93), or the placebo group (n=184). The proportion of patients at week 52 with an SRI-4 response was similar between anifrolumab 300 mg (65 [36%] of 180) and placebo (74 [40%] of 184; difference −4·2 [95% CI −14·2 to 5·8], p=0·41). Similarly, proportions of patients with an SRI-4 response at week 24, and at week 52 in patients in the interferon gene signature test—high subgroup, did not differ between the anifrolumab and placebo groups. In patients with baseline oral corticosteroids of at least 10 mg/day, sustained dose reduction to 7·5 mg/day or less was achieved by 42 (41%) of 103 patients in the anifrolumab 300 mg group and 33 (32%) of 102 patients in the placebo group (difference 8·9 [95% CI −4·1 to 21·9]). In patients with CLASI activity score of at least 10 at baseline, at least 50% reduction by week 12 was achieved by 24 (42%) of 58 patients in the anifrolumab 300 mg group and 14 (25%) of 54 in the placebo group (difference 17·0 [95% CI −0·3 to 34·3]). Annualised flare rates were 0·60 for anifrolumab and 0·72 for placebo (rate ratio 0·83 [95% CI 0·60 to 1·14]). BICLA response was achieved by 67 (37%) of 180 patients receiving anifrolumab 300 mg versus 49 (27%) of 184 receiving placebo (difference 10·1 [95% CI 0·6 to 19·7]). Anifrolumab's safety profile was similar to that observed in phase 2, with similar proportions of patients having a serious adverse event between groups (25 [14%] of 180 for anifrolumab 300 mg, ten [11%] of 93 for anifrolumab 150 mg, and 30 [16%] of 184 for placebo). Interpretation The primary endpoint was not reached. However, several secondary endpoints, including reduction in oral corticosteroid dose, CLASI responses, and BICLA responses, suggest clinical benefit of anifrolumab compared with placebo. Conclusive evidence for the efficacy of anifrolumab awaits further phase 3 trial data. Despite the inherent limitations of a 1-year phase 3 study, such as incomplete knowledge of applicability to the general population and scarce detection of rare safety signals, in addition to complications from prespecified restricted medication rules, our results suggest that anifrolumab might have the potential to provide a treatment option for patients who have active SLE while receiving standard therapy. Funding AstraZeneca.

/pdf/type-i-interferon-inhibitor-anifrolumab-in-active-systemic-4v821qpf3f.pdf

Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial

The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.

/pdf/baff-and-baff-receptor-in-b-cell-selection-and-survival-290ruyosrx.pdf

BAFF and BAFF-Receptor in B Cell Selection and Survival.

Objectives Evaluate efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that binds and neutralises membrane and soluble B-cell activating factor (BAFF) versus placebo plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE). Methods This phase III, 52-week study randomised 1164 patients with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment—SLE Disease Activity Index ≥6 at baseline). Patients received SoC plus subcutaneous injections of tabalumab or placebo, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every two weeks (120 Q2W, n=387), 120 mg every four weeks (120 Q4W, n=389) or placebo Q2W (n=388). Primary endpoint: proportion of patients achieving SLE Responder Index 5 (SRI-5) response at week 52. Results Similar proportions of patients in each group achieved SRI-5 response at week 52 (120 Q2W: 31.8%; 120 Q4W: 35.2% and placebo: 29.3%). Key secondary endpoints were not met. In a sensitivity analysis not excluding patients who decreased antimalarials or immunosuppressants, SRI-5 response was achieved with 120 Q4W (37.0% vs 29.8% placebo; p=0.021), but not 120 Q2W (34.1%; p=0.171). Significant reductions in anti-dsDNA antibodies, increases in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab. No differences were observed between treatment groups in percentage of deaths (120 Q2W: 0.8%; 120 Q4W: 0.5%; placebo: 0.5%), serious adverse events (AEs) (range 11.1–14.4%) or treatment-emergent AEs (range 81.1–82.3%). Conclusions Tabalumab had biological activity—changes in anti-dsDNA, complement, B cells and immunoglobulins—consistent with BAFF pathway inhibition. Key clinical efficacy endpoints did not achieve statistical significance. Safety profiles were similar with tabalumab and placebo. Trial registration number NCT01196091.

https://ard.bmj.com/content/annrheumdis/75/2/323.full.pdf

Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study

Background Tabalumab is a human IgG4 monoclonal antibody that binds and neutralizes membrane and soluble BAFF. Objectives Two trials, involving >2000 patients (pts) with SLE, evaluated the efficacy and safety of subcutaneous tabalumab + standard of care (SoC) versus placebo (pbo) + SoC at 52 weeks (wks). Methods ANA-positive pts were enrolled with active, moderate-to-severe SLE (baseline SELENA-SLEDAI score ≥6). Pts with severe active renal or CNS disease were excluded. Pts received a loading dose (240 mg or pbo) at Wk 0, followed by 120 mg tabalumab every 2 wks (120 Q2W), 4 wks (120 Q4W), or pbo. Primary endpoint: proportion of pts achieving SLE Responder Index 5 (SRI-5) response at Wk 52. Key secondary endpoints: time to severe flare, corticosteroid sparing, and worst fatigue over last 24 hours (hrs). Subgroup analyses based on background SoC, complement, and anti-dsDNA were conducted. Results Baseline disease activity and clinical characteristics were balanced across groups in both trials. SRI-5 was not met in Trial 1, but was met in Trial 2 for the 120 Q2W dose (p=0.002; Table). Key secondary efficacy endpoints did not achieve statistical significance. Subgroup analysis showed that baseline antimalarial (AM) use did not reduce SRI-5 response rates. Reduction in anti-dsDNA was observed as well as increases in complement C3 and C4 and reduction in total B cells and immunoglobulins (Ig). The safety profile of the tabalumab and pbo groups was similar across both trials. Conclusions Tabalumab had biologic activity consistent with BAFF inhibition, as shown by anti-dsDNA, complement, B cell, and Ig changes. The primary endpoint was met in 1 of 2 trials for the 120 Q2W dose. Disclosure of Interest D. Isenberg Consultant for: Eli Lilly and Company, J. Merrill Grant/research support from: GlaxoSmithKline, Consultant for: Eli Lilly and Company, GlaxoSmithKline, Anthera Pharmaceuticals, EMD Serono, Speakers bureau: GlaxoSmithKline, R. Hoffman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Linnik Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Morgan-Cox Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Veenhuizen Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, N. Iikuni Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, C. Dickson Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Silk Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Wallace Consultant for: Eli Lilly and Company, T. Dorner Consultant for: Eli Lilly and Company, UCB, Roche/Chugai Pharmaceutical Co. Ltd., Sanofi

https://ard.bmj.com/content/annrheumdis/74/Suppl_2/141.1.full.pdf

OP0184 Efficacy and Safety of Tabalumab in Patients with Systemic Lupus Erythematosus (SLE): Results from 2 Phase 3, 52-Week, Multicenter, Randomized, Placebo-Controlled Trials

Efficacy and safety of tabalumab in patients with systemic lupus erythematosus (sle): results from 2 phase 3, 52-week, multicenter, randomized, placebo-controlled trials

N Iikuni

Papers

Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study

OP0184 Efficacy and Safety of Tabalumab in Patients with Systemic Lupus Erythematosus (SLE): Results from 2 Phase 3, 52-Week, Multicenter, Randomized, Placebo-Controlled Trials

Efficacy and safety of tabalumab in patients with systemic lupus erythematosus (sle): results from 2 phase 3, 52-week, multicenter, randomized, placebo-controlled trials