SYSTEMIC LUPUS ERYTHEMATOSUS (G TSOKOS, SECTION EDITOR)
New Trials in Lupus and where Are we Going
Joan T. Merrill
Published online: 3 May 2018
Springer Science+Business Media, LLC, part of Springer Nature 2018
Purpose of Review To review progress in the field of clinical trials for SLE.
Recent Findings Treatment development for SLE has been marked by failures of many later phase studies, representing billions
of dollars of lost research and development funding. Recently, more successful Phase II trials have tested reductions in back-
ground medications, novel stringent endpoints, and identification of informative immunologic subsets to achieve greater treat-
ment effects. A large number of agents with promising novel biologic mechanisms have continued to enter clinical development,
and momentum is building to capitalize on newer strategies for trial designs.
Summary Widespread SLE drug development is proceeding despite setbacks and controversies. Approaches focusing on pa-
tients with high disease activity, reduction of background polypharmacy, or increased endpoint stringency provide strategies that
might improve interpretation of trial results. Pharmacodynamics of immune-modulation is a field in its infancy, but ripe for
Keywords Systemic lupus erythematosus
Despite a pressing need to develop more effective and less
toxic immune modulating therapies for systemic lupus
(SLE), little tangible progress has been evident in recent years.
Approval of belimumab by the FDA in 2011 permitted guard-
ed optimism ; nonetheless, other inhibitors of the
BlyS/APRIL pathway failed to show benefit in late phase
trials. Empiric use of off-label treatments remains the standard
of care for this complex disease that is associated with signif-
icant morbidity and socioeconomic burden . Understanding
SLE immunopathology is, however, evolving and lessons
learned from failed studies are gradually being incorporated
in drug development programs. In this review, we focus on
later phase clinical trials for SLE during the past 5 years, pro-
viding our understanding of progress in this field.
Targeting B Cells
Because of their ubiquitous role in SLE pathogenesis , B
cells have been a prime target for a range of biologics .
Unfortunately, neither direct B cell modulation nor B cell de-
pletion were successful in clinical trials. However, a large
anecdotal literature has resulted in rituximab being used wide-
ly around the world for lupus, leaving the optimal role for B
cell targeted agents in SLE unsettled.
B Cell Depletion: Ongoing Questions
Rituximab targets CD20 on circulating B cells, leading to al-
most immediate and often prolonged depletion of these cells.
Even after the failure of two pivotal trials, EXPLORER for
general SLE  and LUNAR for lupus nephritis , rituximab
is still widely used for severe SLE. This has led to an ongoing
debate on how effective it really is and more importantly how
best to select and monitor patients on treatment, since even
believers are aware that a failed trial provides little in the way
of guidance for optimal administration. To the extent that the
depth of B cell depletion corresponds to efficacy, evaluation of
B cells subsets by high sensitivity flow cytometry could help
inform therapeutic decisions. In a prospective series of 125
patients treated with rituximab, the degree of B cell depletion
6 weeks post-therapy did predict clinical response (OR 3.22,
This article is part of the Topical Collection on Systemic Lupus
* Aikaterini Thanou
Arthritis and Clinical Immunology Research Program, Oklahoma
Medical Research Foundation, 825 NE 13th Street, MS 22,
Oklahoma City, OK 73104, USA
Current Rheumatology Reports (2018) 20: 34