Cutaneous manifestations occur frequently in systemic lupus erythematosus (SLE) and are pathognomonic in subacute-cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Although B-cell depletion therapy (BCDT) has demonstrated efficacy in SLE with visceral involvement, its usefulness for patients with predominant skin manifestations has not been fully established. In this single-centre, retrospective study 14 consecutive SLE, one CCLE and two SCLE patients with recalcitrant skin involvement were treated with 2 × rituximab 1 g, and 1 × cyclophosphamide 750 mg.Six months after BCDT, nine of 17 (53%) patients were in complete (CR) or partial remission (PR). Relapses occurred in 12 patients (71%) at a mean time of 10 ± 1.8 months after BCDT. A second cycle of BCDT achieved a more sustained remission in seven of nine patients (78%) lasting for a mean time of 18.4 ± 2.7 months. Minor adverse events were experienced by three patients. Mean follow-up was 30 months.Our own results and the literature review demonstrate that BCDT based on rituximab is well tolerated and may be effective for cutaneous lesions of lupus erythematosus. Randomized controlled trials are necessary to further evaluate the value of BCDT for this group of patients.

B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. The mechanism of action is unclear, but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis.

BackgroundActivated T cells make a significant contribution to inflammation in systemic lupus erythematosus (SLE). Their ability to secrete proinflammatory cytokines and express activating NK receptors allows them to mediate inflammation. We know that cellular metabolism regulates the activation of T cells. A phase II study has reported on efficacy of DMF in cutaneous lupus [1]. Evidence from patients with multiple sclerosis indicates that dimethyl fumarate (DMF), an electrophile, targets cellular metabolism to modulate T cell activation and function [2]. However, the potential of DMF to modulate T cell metabolism and activation in SLE is not known.ObjectivesWe investigated whether DMF modulates T cell metabolism, activation and function in samples from patients with SLE in a series of in vitro experiments.MethodsAll experiments were performed using isolated T cells from freshly drawn whole blood samples from patients with SLE. T cells were isolated using negative selection using Stem cell or Miltenyei magnetic bead separation kit. Isolated T cells were activated with anti-CD3 and IL-2 and incubated with either DMF at 25μM concentration or DMSO alone for three or seven days at 37°C and 5% CO2 before harvesting and analysing on BD FACS flow cytometer.Analysis of cytokines in supernatants was performed using cytometric bead arrays.Flow jo software was used to analyse flow cytometry files.Graph Pad Prism software was used to perform statistical analysis.ResultsIn Seahorse experiments, after three days of incubation dimethyl fumarate (DMF) inhibited the oxygen consumption rate (OCR) and extra cellular acidification rate (ECAR) in isolated T cells when compared with samples incubated with vehicle, dimethyl sulfoxide (DMSO).Our results revealed that DMF significantly inhibited: 1) aerobic glycolysis and oxidative phosphorylation in activated CD4+T cells from patients with SLE (n=4), in vitro; 2) T cell activation and proliferation as assessed by a reduction in the frequency of CD69 (n=4) and Ki67 (n=2) positivity, respectively. Collectively, these results suggest that DMF inhibits T cell activation and proliferation in samples from patients with SLE.After 7 days of incubation, DMF significantly inhibited the expression of activating NK receptors CD158a and NKG2D on CD4+T cells whereas DMF seemed to have a trend toward enhancing the expression of inhibitory NK receptors NKG2A and CD158b (n=6).After 7 days of incubation, DMF significantly reduced CD4+T cell intracellular expression of IFN-γ, TNF-α, IL-17 and secretion of pro-inflammatory cytokines IFN-γ and TNF-α in supernatants (n=6).ConclusionOur data indicated that DMF modulates metabolic programming, both glycolysis and oxidative phosphorylation, to inhibit activation, proliferation, and secretion of proinflammatory cytokines from CD4+T cells from patients with SLE. These results provide strong mechanistic rationale for considering dimethyl fumarate as a novel therapeutic agent to treat systemic lupus erythematosus.References[1]Kuhn A, Landmann A, Patsinakidis N, Ruland V, Nozinic S, Perusquia Ortiz AM, et al. Fumaric acid ester treatment in cutaneous lupus erythematosus (CLE): a prospective, open-label, phase II pilot study. Lupus. 2016;25(12):1357-64.[2]Kornberg MD, Bhargava P, Kim PM, Putluri V, Snowman AM, Putluri N, et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science. 2018;360(6387):449-53.AcknowledgementsThe study received full funding support from the biomedical research centre, University College Hospital. Dr. Reddy’s work was supported by MRC-CARP fellowship award.Disclosure of InterestsLoren Kell: None declared, Samuel Taylor: None declared, Kavina Shah: None declared, Roel De Maeyer: None declared, David Isenberg Consultant of: no competing interest with submitted work, Grant/research support from: no competing interest with submitted work, Madhura Castelino: None declared, Geraldine Cambridge: None declared, Debajit Sen: None declared, Maria José Leandro Consultant of: no competing interest with submitted work, Grant/research support from: Roche Glycart, Arne Akbar: None declared, Venkat Reddy Grant/research support from: Roche Glycart, no competing interest with submitted work.

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BackgroundB cells infiltrate the kidneys of LN pts, and leukocyte-rich tubulointerstitial infiltrates are associated with greater risk for progression to renal failure. High-sensitivity flow cytometry (HSFC) analysis suggests incomplete B-cell depletion in systemic lupus erythematosus (SLE) is associated with nonresponse to rituximab (RTX). Obinutuzumab (Obi) is a glycoengineered type 2 anti-CD20 mAb that binds CD20 differently from RTX, a conventional type 1 anti-CD20 mAb, and depletes B cells to a greater degree than RTX. In preclinical studies, Obi displayed significantly increased antibody-dependent cellular cytotoxicity and enhanced direct cell death over type 1 anti-CD20 mAbs. In the CLL11 trial, which led to FDA breakthrough designation and its licensing in chronic lymphocytic leukemia, Obi demonstrated greater progression-free survival and greater minimal residual disease negativity over RTX even in protected microenvironments such as bone marrow. Double-blind randomized controlled trials demonstrated that type 1 anti-CD20 mAbs added to mycophenolate mofetil (MMF) or cyclophosphamide (CYC) increased the proportions of pts achieving partial renal response (PRR) but had no impact on complete renal response (CRR) rates at 12 months. Although these studies with RTX and ocrelizumab did not meet their respective primary endpoints, EULAR and ACR LN guidelines recommend RTX if treatment with CYC or MMF fails.ObjectivesThe phase 2 study NOBILITY is designed to test the hypothesis that Obi may generate superior CRR rates in pts with active proliferative LN based on its ability to deplete B cells to a greater degree than type 1 anti-CD20 mAbs. The primary objective of this study is to evaluate the effect of Obi compared with placebo (PBO) when added to MMF in pts with class III or IV LN as assessed by the proportion of pts who achieve CRR at wk 52. Key secondary objectives relate to overall response (CRR + PRR), PRR, change in biomarkers of LN disease activity, and time to CRR.MethodsRandomized, double-blind, PBO-controlled study to evaluate safety and efficacy of Obi added to MMF and corticosteroids (CS) in pts with ISN/RPS 2003 class III or IV LN.ResultsThe study design is as follows: NOBILITY is a global multicenter study enrolling ∼120 pts with biopsy-proven ISN/RPS 2003 class III or IV LN in the United States, Mexico, Columbia, Argentina, Spain, Israel, Brazil, and France. All pts will be on MMF up to 2.5 g/d and a combination of IV and oral CS to be tapered to 7.5 mg/d by wk 12. All pts will be followed up until wk 104, with the primary endpoint evaluation at wk 52 (figure). NOBILITY also features interim analyses at wk 4 for depletion of peripheral CD19+ B cells by HSFC, centralized evaluation of the renal biopsy, and repeat renal biopsy on the basis of clinical status and local practice.ConclusionsNOBILITY, a phase 2 trial evaluating Obi in LN, is grounded on the hypothesis that a type 2 anti-CD20 mAb will induce greater B-cell depletion in the kidneys and associated secondary lymphoid structures, translating...