patient care perspectives

Therapeutic Developments in Systemic Lupus Erythematosus: Treatment and Maintenance

by Joan T. Merrill, MD


Developments in systemic lupus erythematosus (SLE) treatment and maintenance therapy include recent data with belimumab in patients with active lupus nephritis as well as the introduction of voclosporin, a newer calcineurin inhibitor. Additionally, promising novel targets are being explored in early phase clinical trials.

Expert Commentary

Joan T. Merrill, MD

Member and Director of Clinical Projects
Arthritis & Clinical Immunology Research Program
Oklahoma Medical Research Foundation
OMRF Professor of Medicine
University of Oklahoma Health Sciences Center
Adjunct Professor of Medicine
New York University Langone Health
Chief Advisor for Clinical Development
Lupus Foundation of America
Oklahoma City, OK

“We are currently moving toward more benign treatments. We used to be predominantly cyclophosphamide based in our approach. Other agents subsequently became available that seemed to work well, so this area has become a bit more fluid in clinical practice.”

Joan T. Merrill, MD

The concept of maintenance derives mainly from lupus nephritis, where aggressive therapy in the first 6 months or longer gives way to lower doses and less aggressive treatment once the SLE is under control. We are currently moving toward more benign treatments. We used to be predominantly cyclophosphamide based in our approach. Other agents subsequently became available that seemed to work well, so this area has become a bit more fluid in clinical practice. The duration of the initial, more aggressive therapy might be 6 or 9 months. Further, we want to verify that the patient’s proteinuria has improved before becoming less aggressive in our approach. After this is verified, we then lower the doses and maintain treatment for quite some time.

Nearly a decade ago, belimumab was studied in a general SLE population. Patients with severe active lupus nephritis were excluded, but a subset had renal involvement at baseline. A post hoc analysis seemed to suggest that there was a signal for improvement in kidney disease with belimumab. Newer data have recently emerged with belimumab in lupus nephritis. The more recent data published in 2020 by Furie et al come from a dedicated phase 3 lupus nephritis study in adults with biopsy-proven, active lupus nephritis, and the results of this trial clearly showed a difference with the addition of belimumab compared with standard therapy alone.

Other targets continue to be of interest in SLE. BLyS, the target of belimumab, acts downstream from the type I interferon-α receptor (IFNAR). Anifrolumab is an IFNAR1 antagonist that was recently approved by the US Food and Drug Administration for adults with moderate to severe SLE who are receiving standard therapy; however, it has not been evaluated for severe active lupus nephritis. Calcineurin inhibitors are thought to work by reducing interleukin-2 production and interleukin-2 receptor expression, leading to a reduction in T-cell activation. The calcineurin inhibitor voclosporin was recently approved in combination with a background therapy regimen for the treatment of active lupus nephritis in adults. 

On the research front, some agents in development act at other points in pathways that are relevant to SLE. IFNAR signaling is transduced and is picked up by JAK1 and TYK2, a nonreceptor tyrosine kinase. TYK2 works with JAK1 or JAK2 to mediate cytokine signaling, including type I IFN signaling, and there is an inhibitor in development (ie, deucravacitinib) that seems to be relatively specific for TYK2. Baricitinib hits JAK1 and JAK2 and was examined in a successful phase 2 trial; I do believe that there was an efficacy signal with baricitinib, but there was a high placebo response rate, which raises questions about the trial design. Telitacicept is a fusion protein that interferes with BLyS/BAFF and APRIL, and investigators did taper steroids in that trial, so I am more confident in that design. Finally, another interesting agent is obexelimab, which engages with FcγRIIb, a natural modulator of immune responses. It tones down B-cell hyperactivity, marshaling what the immune system already has in place.

References Long-term safety and efficacy study of deucravacitinib in participants with systemic lupus erythematosus. Updated October 26, 2021. Accessed September 28, 2021.

Davis LS, Reimold AM. Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus. Rheumatology (Oxford). 2017;56(suppl 1):i100-i113. doi:10.1093/rheumatology/kew417

Ding Y, Zack D, Burington B, et al. A novel biomarker identifies systemic lupus erythematous (SLE) patients who benefit from obexelimab (XmAb®5871) treatment [abstract 1840]. Abstract presented at: ACR Convergence 2020; November 5-9, 2020.

Dooley MA, Houssiau F, Aranow C, et al; BLISS-52 and -76 Study Groups. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus. 2013;22(1):63-72. doi:10.1177/0961203312465781

Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736-745. doi:10.1136/annrheumdis-2019-215089

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):1117-1128. doi:10.1056/NEJMoa2001180

Mathian A, Pha M, Haroche J, et al. Withdrawal of low-dose prednisone in SLE patients with a clinically quiescent disease for more than 1 year: a randomised clinical trial. Ann Rheum Dis. 2020;79(3):339-346. doi:10.1136/annrheumdis-2019-216303

Mathias LM, Stohl W. Systemic lupus erythematosus (SLE): emerging therapeutic targets. Expert Opin Ther Targets. 2020;24(12):1283-1302. doi:10.1080/14728222.2020.1832464

Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial [published correction appears in Lancet. 2018;392(10146):476]. Lancet. 2018;392(10143):222-231. doi:10.1016/S0140-6736(18)31363-1

Whitehouse G, Gray E, Mastoridis S, et al. IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors. Proc Natl Acad Sci U S A. 2017;114(27):7083-7088. doi:10.1073/pnas.1620835114

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