Contributors: Consulting Editor

Systemic Lupus Erythematosus
Contributors
CONSULTING EDITOR
MICHAEL H. WEISMAN, MD
Director, Division of Rheumatology; Professor of Medicine, Cedars-Sinai Medical Center,
Los Angeles, California
EDITORS
ELLEN M. GINZLER, MD, MPH

Distinguished Teaching Professor of Medicine, Division of Rheumatology, State University
of New York Downstate Medical Center, Brooklyn, New York
MARY ANNE DOOLEY, MD, MPH

Associate Professor of Medicine, Division of Rheumatology and Immunology, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
AUTHORS
GRACIELA S. ALARCÓN, MD, MPH, MACR

Division of Clinical Immunology and Rheumatology, Department of Medicine, School of
Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
ANTHONY ALVARADO, MD
Nephrology Division, Department of Internal Medicine, Ohio State University Wexner
Medical Center, Columbus, Ohio
ANCA D. ASKANASE, MD, MPH

Department of Medicine, Columbia University Medical Center, New York, New York
SANG-CHEOL BAE, MD, PhD, MPH

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases,
Seoul, Republic of Korea
SASHA BERNATSKY, MD, PhD

Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Quebec,
Canada
CHAN-BUM CHOI, MD, PhD

Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases,
Seoul, Republic of Korea; Department of Aging, Brigham and Women’s Hospital; Section
of Rheumatology, VA Healthcare System, Boston, Massachusetts
ANN E. CLARKE, MD, MSc

Division of Rheumatology, University of Calgary, Calgary, Alberta, Canada
Downloaded from ClinicalKey.com at Univ Targu Mures Med Pharmacy March 31, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
iv Contributors
JAN P. DUTZ, MD
Department of Dermatology and Skin Science; Child and Family Research Institute,
University of British Columbia, Vancouver, British Columbia, Canada
LUIS ALONSO GONZÁLEZ, MD

Division of Rheumatology, Department of Internal Medicine, School of Medicine,
Universidad de Antioquia, Medellı́n, Antioquia, Colombia
CAROLINE GORDON, MD
Division of Rheumatology, College of Medical and Dental Sciences, University of
Birmingham, Edgbaston, United Kingdom
SAMAR GUPTA, MD
Section of Rheumatology, VA Healthcare System, Boston, Massachusetts
JAMES E. HANSEN, MD
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut
JUDITH A. JAMES, MD, PhD

Department of Arthritis and Clinical Immunology, Oklahoma Medical Research
Foundation; Oklahoma Clinical & Translation Science Institute; Departments of Medicine,
Pathology, and Microbiology & Immunology, University of Oklahoma Health Sciences
Center, Oklahoma City, Oklahoma
DIANE L. KAMEN, MD, MS

Associate Professor of Medicine, Division of Rheumatology and Immunology, Depart-
ment of Medicine, Medical University of South Carolina, Charleston, South Carolina
MARK G. KIRCHHOF, MD, PhD

Department of Dermatology and Skin Science, University of British Columbia, Vancouver,
British Columbia, Canada
MATTHEW H. LIANG, MD, MPH

Professor of Medicine, Section of Rheumatology, VA Healthcare System, Boston,
Massachusetts
MAUREEN MCMAHON, MD, MS

Associate Clinical Professor of Medicine, Division of Rheumatology, David Geffen School
of Medicine, University of California, Los Angeles, Los Angeles, California
CHARLES T. MOLTA, MD, FACR

GlaxoSmithKline, Philadelphia, Pennsylvania
SAMIR V. PARIKH, MD
ROSALIND RAMSEY-GOLDMAN, MD, DrPh

Division of Rheumatology, Northwestern University Feinberg School of Medicine,
Chicago, Illinois
MALCOLM P. ROGERS, MD
Tufts University, Boston, Massachusetts
BRAD H. ROVIN, MD
Contributors v
BRIAN SKAGGS, PhD

Division of Rheumatology, David Geffen School of Medicine, University of California,
Los Angeles, Los Angeles, California
BASILE TESSIER-CLOUTIER, MD
Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Quebec,
Canada
SERGIO M.A. TOLOZA, MD

Department of Medicine, Rheumatology Unit, Hospital San Juan Bautista, San Fernando
del Valle de Catamarca, Catamarca, Argentina
MICHAEL M. WARD, MD
Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin
Diseases, National Institutes of Health, Bethesda, Maryland
JINOOS YAZDANY, MD, MPH

Department of Medicine, University of California, San Francisco, School of Medicine,
San Francisco, California
Contents
Foreword xi
Michael H. Weisman
Preface: Systemic Lupus Erythematosus xiii

Ellen M. Ginzler and Mary Anne Dooley
Environmental Influences on Systemic Lupus Erythematosus Expression 401

Diane L. Kamen
The etiology of systemic lupus erythematosus (SLE) is unknown, but
multiple genetic, epigenetic, and environmental risk factors have been
implicated. The inheritance of genes alone is not sufficient for developing
SLE, suggesting the influence of environmental triggers on disease
expression. Despite the tremendous amount of progress in elucidating
potential environmental risk factors for SLE, much more needs to be
done. An interdisciplinary approach to studies of the causes and, ulti-
mately, prevention of SLE is needed. This article reviews what is under-
stood about the relationship between environmental exposures and SLE,
in addition to emerging areas of study.
Clinical Perspectives on Lupus Genetics: Advances and Opportunities 413

Judith A. James
In recent years, genome-wide association studies have led to an expansion
in the identification of regions containing confirmed genetic risk variants
within complex human diseases, such as systemic lupus erythematosus
(SLE). Many of the strongest SLE genetic associations can be divided
into groups based on their potential roles in different processes implicated
in lupus pathogenesis, including ubiquitination, DNA degradation, innate
immunity, cellular immunity, lymphocyte development, and antigen pre-
sentation. Recent advances have also shown several genetic associations
with SLE subphenotypes and subcriteria. Many areas for further explora-
tion remain to move lupus genetic studies toward clinically informative
end points.
Impact of Race and Ethnicity in the Course and Outcome of Systemic Lupus
Erythematosus 433
Luis Alonso González, Sergio M.A. Toloza, and Graciela S. Alarcón
Genetic factors seem to play a more important role early in the course of
systemic lupus erythematosus (SLE), whereas nongenetic factors seem
to play a more important role over the course of the disease. SLE is
more frequent with less favorable outcomes in nonwhite populations. To
overcome these differences and reduce the immediate-term, mediate-
term, and long-term impact of SLE among disadvantaged populations, it
is essential to increase disease awareness, to improve access to health
viii Contents
care and to provide care to these patients in a consistent manner regard-

less of the severity of their disease.
The Immunopathology of Cutaneous Lupus Erythematosus 455

Mark G. Kirchhof and Jan P. Dutz
Systemic lupus erythematosus (SLE) is an autoimmune disease that is
characterized by the development of autoantibodies and immunologic
attack of different organ systems, including the skin. This review aims to
provide an overview of some of the pathogenic processes that may be
important in the development of SLE, specifically cutaneous lupus erythe-
matosus, and then illustrates how therapies might be tailored to modify
these processes and treat disease.
Pathogenesis and Treatment of Atherosclerosis in Lupus 475

Maureen McMahon and Brian Skaggs
The prevalence of atherosclerosis (ATH) is higher in patients with systemic
lupus erythematosus (SLE) and occurs at an earlier age. The lupus-related
factors that account for this increased risk are likely numerous and related
to the factors described in this article. Identifying of at-risk subjects and
increasing the understanding of pathogenesis of ATH in SLE is critical
for improving the quality of care and improving mortality in this vulnerable
population.
Systemic Lupus Erythematosus and Malignancies: A Review Article 497

Basile Tessier-Cloutier, Ann E. Clarke, Rosalind Ramsey-Goldman,
Caroline Gordon, James E. Hansen, and Sasha Bernatsky
The systemic lupus erythematosus (SLE) population has a unique cancer
risk profile. This article presents the most recent data on risk of cancer
in lupus and discusses possible contributing factors. The risk of lymphoma
is particularly increased in SLE and may be mediated by immunosuppres-
sive medication. Lung cancer risk is also increased in SLE. There is a high
rate of cervical dysplasia in women with SLE. A similar pathophysiology
could be responsible for the trend seen in vulvovaginal and hepatic carci-
nomas. There is a decreased risk in SLE for some hormone-sensitive can-
cers, but the cause of this remains unclear.
Post-marketing Experiences with Belimumab in the Treatment of SLE Patients 507

Anca D. Askanase, Jinoos Yazdany, and Charles T. Molta
Belimumab (Benlysta) is a human recombinant monoclonal antibody that
targets and inhibits soluble B-lymphocyte stimulator, also known as
B-cell activating factor, a proliferation and survival factor for B cells. The
published clinical trials data showed that in patients with active systemic
lupus erythematosus (SLE), belimumab effectively reduced peripheral
B-cell levels and improved disease activity. This article reviews the belimu-
mab clinical trials and the post-marketing experience with belimumab in
the treatment of those lupus patients with persistent active disease despite
current standard of care (SOC) therapy.
Contents ix
Recent Clinical Trials in Lupus Nephritis 519

Michael M. Ward
Recent clinical trials have provided evidence for the efficacy of low-dose
intravenous cyclophosphamide and mycophenolate mofetil as induction
treatment for patients with proliferative lupus nephritis in comparative trials
with standard-dose intravenous cyclophosphamide. Trials of maintenance
treatments have had more variable results, but suggest that the efficacy of
mycophenolate mofetil may be similar to that of quarterly standard-dose
intravenous cyclophosphamide and somewhat more efficacious than
azathioprine. Differential responses to mycophenolate mofetil based on
ethnicity suggest that it may be more effective in black and Hispanic
patients. Rituximab was not efficacious as an adjunct to induction treat-
ment with mycophenolate mofetil.
The Kidney Biopsy in Lupus Nephritis: Is It Still Relevant? 537

Brad H. Rovin, Samir V. Parikh, and Anthony Alvarado
The kidney biopsy is the standard of care for diagnosis of lupus nephritis
and remains necessary to ensure accurate diagnosis and guide treatment.
Repeat biopsy should be considered when therapy modifications are
necessary, as in cases with incomplete or no response, or when stopping
therapy for those in remission. There are several promising biomarkers of
kidney disorders; however, these markers need to be validated in a pro-
spective clinical trial before being applied clinically. Molecular analysis
may provide the information presently lacking from current evaluation of
kidney disorders and may better inform on prognosis and treatment
considerations.
Improving Participation in Clinical Trials of Novel Therapies: Going Back to Basics 553
Chan-Bum Choi, Sang-Cheol Bae, Samar Gupta, Malcolm P. Rogers, and
Matthew H. Liang
Clinical trials in many diseases are experiencing more difficulties in achiev-
ing sufficient or timely enrollment of participants; anecdotal reports from
trials of novel therapies for systemic lupus erythematosus (SLE) seem to
be facing the same challenges. General factors associated with this trend
include the growth of the contract research industry, increasing oversight,
and high-profile accounts of scientific misconduct and fraud in research.
Complicated protocols that increase participant burden, overly restrictive
entry criteria, the fear of an SLE flare may also affect enrollment in SLE
trials.
Index 561
x Systemic Lupus Erythematosus
RHEUMATIC DISEASE CLINICS

OF NORTH AMERICA
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Pediatric Rheumatology
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RELATED INTEREST
Pediatric Clinics of North America, April 2012 (Volume 59, Issue 2)
Pediatric Rheumatology
Ronald M. Laxer and David D. Sherry, Editors
Neurologic Clinics, February 2010 (Volume 28, Issue 1)

Neurologic Manifestations of Systemic Lupus Erythematosus in Children and
Adults in Children and Adults
Eyal Muscal and Robin L. Brey, Editors
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Foreword
Michael H. Weisman, MD
Consulting Editor
Doctors Ginzler and Dooley have accomplished what was totally expected by me—a
concise and up-to-date review of lupus in the areas of genetic predisposition, epige-
netic influences, environmental triggers, immune-pathologic mechanisms of organ
damage, epidemiology regarding race and other influences on prevalence and severity,
and the comorbidities that plague lupus patients regarding cardiac disease and malig-
nancy potential. In addition, they have educated the reader on what clinical trial data
have taught us about disease management with agents that have a targeted focus,
emphasizing the limitations posed by these data and suggestions on how to make
the next steps more robust and productive. Finally, we have two superb articles on
lupus nephritis each written by experts in the field that attack the problem from different
points of view. The choices of authors and the responses by these experts have given
great credibility to this volume, and we are proud of this issue and expect a real impact
on the education of our colleagues and anyone involved in the field of lupus.
Michael H. Weisman, MD
Division of Rheumatology
Cedars-Sinai Medical Center
8700 Beverly Boulevard
Los Angeles, CA 90024, USA
E-mail address:
michael.weisman@cshs.org
Rheum Dis Clin N Am 40 (2014) xi

http://dx.doi.org/10.1016/j.rdc.2014.06.001 rheumatic.theclinics.com
0889-857X/14/$ – see front matter Ó 2014 Published by Elsevier Inc.
Preface
Ellen M. Ginzler, MD, MPH Mary Anne Dooley, MD, MPH

Editors
The last issue of Rheumatic Disease Clinics of North America to cover systemic lupus
erythematosus (SLE) was published in February 2010. In only the last four years, there
have been dramatic changes in our understanding of the immunology, genetic/
epigenetic associations, and identification of new targets for therapy in this multifac-
eted disease. We are very excited to have invited a superb group of authors to
present articles detailing cutting-edge advances in these areas.
The initial series of articles cover the review of interactions between environmental
exposures on disease susceptibility and presentation by Kamen, the update on lupus
genetics and gene/environment interactions by James, and the discussion by Gonzalez
and coworkers of the contribution of race and ethnicity to disease prevalence, expres-
sion, and response to therapy.
Advances in our knowledge of pathophysiologic processes have clearly informed
our understanding of organ-specific disease features and long-term risk of irreversible
damage. The article by Kirchhof and Dutz provides an excellent review of the immuno-
logic processes and triggers contributing to the cutaneous manifestations of SLE and
implications for new therapeutic modalities. McMahon and Skaggs review the lupus-
specific risks and biomarkers for accelerated atherosclerosis, which contribute to
the high burden of morbidity and mortality among lupus patients. Tessier Cloutier
and colleagues discuss the unique cancer risk profile in patients with lupus, including
new data on incidence, prevalence, and contributing factors.
Each of these previous articles may suggest new approaches to therapy. At
the same time, there have been exciting advances in the therapeutic armamentarium
for SLE. The first new medication for SLE approved by the FDA occurred in 2011;
Askenase and coworkers summarize the clinical trials data for Benlysta (belimumab)
and review the postmarketing experience with this biologic agent. Ward provides a
critical assessment of the recent clinical trials in lupus nephritis, noting that compari-
son among studies is hampered by differences in patient populations, outcome mea-
sures, and response criteria. Suggestions for remediating these issues are provided in
Rheum Dis Clin N Am 40 (2014) xiii–xiv

0889-857X/14/$ – see front matter Ó 2014 Published by Elsevier Inc.
xiv Preface
the article by Rovin and colleagues, with recommendations for repeat renal biopsy
after therapeutic interventions and potential use of molecular diagnostics to validate
noninvasive biomarkers, allowing for personalized therapy. Finally, Choi and co-
workers discuss the critical importance of improving enrollment in lupus clinical trials,
recommending changes in trial design, and the approach to the patient with SLE.
Ellen M. Ginzler, MD, MPH

Division of Rheumatology
State University of New York Downstate Medical Center
450 Clarkson Avenue
Brooklyn, NY 11203, USA
Mary Anne Dooley, MD, MPH
Division of Rheumatology and Immunology
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599, USA
E-mail addresses:
ellen.ginzler@downstate.edu (E.M. Ginzler)
mary_dooley@med.unc.edu (M.A. Dooley)
E n v i ro n m e n t a l In f l u e n c e s
on Systemic Lupus
E r y t h e m a t o s u s E x p res s i o n
Diane L. Kamen, MD, MS
KEYWORDS
Systemic lupus erythematosus Etiology Vitamin D Environment Risk factors
KEY POINTS
The etiology of systemic lupus erythematosus (SLE) is unknown, but multiple genetic,
epigenetic, and environmental risk factors have been implicated.
The inheritance of genes alone is not sufficient for developing SLE, suggesting the influ-
ence of environmental triggers on disease expression.
Despite the tremendous amount of progress in elucidating potential environmental risk
factors of SLE, much more needs to be done.
An interdisciplinary approach to studies of the causes and, ultimately, the prevention of
SLE is needed.
INTRODUCTION
Systemic lupus erythematosus (SLE) is a chronic and potentially severe systemic

autoimmune disease that disproportionately affects young women, African Ameri-
cans, and Hispanics.1–4 The etiology of SLE is unknown, but multiple genetic, epige-
netic, and environmental risk factors have been implicated. The inheritance of genes
alone is not sufficient for developing SLE, suggesting the influence of environmental
triggers on disease expression.
It is known that SLE develops through multiple steps, with the loss of self-tolerance
and development of autoantibodies occurring sometimes several years before the
onset of clinically symptomatic autoimmune disease.5,6 Although first-degree relatives
Disclosure Statement: The author declares that she has no conflicts of interest or financial
disclosures.
Dr D.L. Kamen’s work was supported by funding from the National Institutes of Health (NIH):
R21 ES017934 from National Institute of Environmental Health Sciences and P60 AR062755
from National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Division of Rheumatology and Immunology, Department of Medicine, Medical University of
South Carolina, 96 Jonathan Lucas Street, Suite 816, Charleston, SC 29425, USA
E-mail address: kamend@musc.edu
Rheum Dis Clin N Am 40 (2014) 401–412

0889-857X/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
402 Kamen
of patients with SLE overall have a higher prevalence of autoantibodies and a higher
risk of SLE and other autoimmune diseases,7,8 some develop SLE-specific autoanti-
bodies but never develop clinical disease,9 implying that there are protective factors
as well. The multifactorial nature of the genetic risk of SLE and the low disease pene-
trance emphasize the potential influence and complexity of environmental factors and
gene-environment interactions on the etiology of SLE.10
Despite the significant role of the environment in modulating autoimmunity patho-
genesis, the specific mechanisms by which it acts remain poorly understood. In
2005, Christopher Paul Wild called for increased resources to be devoted to studies
of the “exposome” to complement the advances that have been made in genome
research.11 Ultimately, methods need to be developed for the measurement of an
individual’s environmental exposures with the same precision that an individual’s
genome is measured. This call has been answered in a small part by “omics” technol-
ogies of transcriptomics, proteomics, and metabolomics, but these investigations are
in their infancy when answering questions regarding SLE etiology.
This article reviews what is understood with regard to the epidemiology of the rela-
tionship between environmental exposures and SLE, in addition to emerging areas of
study.
INTERPLAY BETWEEN ENVIRONMENTAL FACTORS, GENETICS, AND EPIGENETICS
Knowledge of the genetic contributions to SLE risk has grown exponentially over the
past decade, and has contributed to recent improvement in understanding the role of
genetic risk factors in SLE (Fig. 1). Each susceptibility gene present in an individual’s
genome contributes to that individual’s relative risk of developing SLE, and can influ-
ence the age of disease onset and clinical manifestations.12 Although more than 50
susceptibility loci for SLE have been discovered to date, these risk loci collectively
explain only a minority of the genetic risk. Utilization of next-generation sequencing
techniques and exploration of gene-gene and genetic-epigenetic interactions are
expected to account for much of the “missing heritability” in SLE.13
Nonencoded regulation of gene expression provided by epigenetic mechanisms
(DNA methylation, modifications of histone tails, and noncoding RNAs) plays a role
in SLE susceptibility that is still being deciphered. These epigenetic modifications
Fig. 1. Interplay between environmental factors, genetics, and epigenetics. Systemic lupus
erythematosus develops through multiple steps, with the loss of self-tolerance and develop-
ment of autoantibodies occurring sometimes several years before the onset of clinically
symptomatic autoimmune disease. EBV, Epstein-Barr virus.
Environmental Influences on SLE Expression 403
can result from both inherited DNA sequences and environmental exposures. Even
monozygotic twins, epigenetically nearly indistinguishable at birth, later develop
important differences in their epigenomic landscape.14 Reduced DNA methylation,
histone hypoacetylation and hyperacetylation, and the overexpression of certain
miRNAs, resulting in altered immune responses, have been associated with the onset
and progression of SLE.15,16 Along these lines, it is interesting that procainamide and
hydralazine can cause drug-induced lupus through epigenetic mechanisms by inhib-
iting DNA methylation in T cells.17
DIETARY INFLUENCES ON SLE
Although alterations in diet can reduce the risk of associated conditions such as
atherosclerosis and metabolic syndrome,18 definitive evidence is lacking that dietary
factors influence the development of human SLE or disease activity. Conflicting results
have been found with certain dietary factors, some of which may have had supporting
evidence from animal models or case reports. For example, an association between
consumption of alfalfa sprouts and development of SLE was seen in the Baltimore
Lupus Environmental Study19; however, a Swedish case-control study found no asso-
ciation between alfalfa sprouts and SLE risk.20
Epigenetic changes in response to diet and other environmental exposures have
important implications for the development of SLE, including potential targets for pre-
vention. Studies by Strickland and colleagues21 have shown in a mouse model of SLE
that manipulation of DNA methylation via changes in dietary methyl donor content can
significantly influence disease susceptibility and severity. Little is known about the
influence of diet on DNA methylation in the pathogenesis of human disease.
Although case-control studies have shown associations between vitamin D levels
and SLE, no association was found between dietary intake of vitamin D and the future
risk of developing SLE among women in the Nurses’ Health Study cohorts.22,23 There
are limitations to relying on self-reported vitamin D intake to represent vitamin D sta-
tus, because dietary sources account for a small proportion of circulating vitamin D,
which is better reflected by measurement of serum 25-hydroxyvitamin D (25(OH)D)
levels. Studies that have examined associations between 25(OH)D levels and SLE
are discussed later.
The Nurses’ Health Study cohorts were also used to examine whether antioxidants
from foods and supplements influenced the future development of SLE. Total anti-
oxidant intake, including vitamins A, C, and E, a-carotene, b-carotene, b-cryptoxanthin,
lycopene, lutein, and zeaxanthin, was not associated with the risk of developing SLE.24
Inability to generalize results outside of the female Caucasian population is a limitation
of the vitamin D and antioxidant intake studies, owing to the demographics of those
enrolled in the Nurses’ Health Study.
Thus far there has been an inadequate extent of investigation into whether other
foods, chemicals in foods, or dietary supplements are associated with the risk or
course of SLE.
ESTABLISHED ENVIRONMENTAL RISK FACTORS FOR SLE
The triggers, mechanisms, and timing of disease development in SLE remain largely
unknown despite many lines of experimental and epidemiologic investigation. Many
potential environmental triggers of SLE have been investigated, often as part of
large-scale epidemiologic studies, but compelling evidence of a causative role has
thus far only been reported with silica dust and, to a lesser extent, smoking and expo-
sure to Epstein-Barr virus (EBV).25
404 Kamen
A National Institute of Environmental Health Sciences (NIEHS) Expert Panel was

convened in 2010 to evaluate levels of confidence about existing research on environ-
mental influences in the development of autoimmune diseases and to identify prom-
ising areas for further investigation.25 Using established guidelines to assess
causality, associations between each exposure and autoimmune disease were classi-
fied as “confident,” “likely,” or “unlikely,” based on published evidence. Many associ-
ations were considered to have “insufficient” data to support classification and were
therefore not included in the published report.
Silica Exposure and SLE

With regard to SLE, the NIEHS Panel determined that occupational exposure to silica
was the only exposure classified as “confident” in its contribution to the development
of disease.25 This finding was based on positive associations between occupational
exposure to silica and development of SLE in 3 population-based case-control
studies26–28 and 3 cohort studies29–31 (659 cases total) from Europe and North
America. The case-control studies used structured interviews and detailed occupa-
tional histories to ascertain exposure status, whereas the cohort studies followed
highly exposed populations. An additional case-control study comparing 51 lupus
nephritis patients with age-, race-, and sex-matched patients with other renal dis-
eases did not find an association with silica exposure ascertained by a self-
administered questionnaire.32
Exposure to particulate silica (crystalline silica or quartz) most commonly comes
from mining and “dusty trades” such as sandblasting, granite cutting, construction
work, cement work, and brick and tile laying. Exposure can also result from proximity
to agricultural work in areas with a high content of silica in soil. The studies of silica
exposure and SLE provide evidence to support a dose response, with higher risk in
those with higher exposure. Overall the estimated risk ratios for SLE ranged from
1.6 (any silica exposure) to 4.9 (high silica exposure) within the general population,
and the risk ratio was greater than 10 among highly exposed populations (ie, people
with silicosis).25
Cigarette Smoking and SLE

Current cigarette smoking was considered by the NIEHS Panel to “likely” contribute
to the development of SLE, based on multiple studies with variable results. A meta-
analysis of smoking and SLE risk studies by Costenbader and colleagues33 found a
modestly increased risk of SLE with current smoking in comparison with never
smoking (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.09–2.08). Based on
the 7 case-control and 2 cohort studies available for the meta-analysis, the risk
with past smoking compared with never smoking was not elevated (OR 0.98, 95%
CI 0.75–1.27).33 By contrast, a more recent case-control study not included in the
meta-analysis, with 223 SLE patients and 1538 controls from Finland, found a higher
risk for SLE with past smoking compared with never smoking (OR 1.80, 95% CI
1.15–2.83).34
Smoking also appears to influence the course of disease among patients with SLE,
particularly skin manifestations, with current smoking associated with active SLE
rashes and having ever smoked being associated with discoid rash and photosensi-
tivity.35 Although cigarette smoke contains hundreds of potentially toxic components,
is unclear whether its influence on SLE is attributable to an individual component or if
the culprit is a mixture of tars, nicotine, carbon monoxide, polycyclic aromatic hydro-
carbons, and/or others.
Smoking and the Role of Gene-Environment Interactions

There is a growing awareness of gene-environment interactions relevant to diseases
such as SLE, which helps explain why individuals respond differently to the same envi-
ronmental exposure and why some may develop disease while others do not. As
genetic risk variants are further defined for SLE, genetic pathway analyses can help
determine potential interactions with certain environmental exposures and potential
differences between demographic groups.
For example, several case-control studies have found a small increased risk of
developing SLE among those who smoke cigarettes, but the risk is higher among
those with certain polymorphisms in genes for metabolic enzymes involved in the pro-
duction of reactive oxygen species. A Japanese case-control study of SLE found that
the combination of smoking and 2 candidate gene polymorphisms in CYP1A1 and
GSTM1 was associated with SLE susceptibility.36
EBV Exposure and SLE

Many infectious agents, including viruses, bacteria, and parasites, have been pro-
posed as triggers of autoimmune diseases, including SLE.37 The infectious agent
with the most compelling evidence to date for contributing to the pathogenesis of
SLE has been EBV.
Epidemiologic data supports a connection between EBV infection and SLE.38,39 In-
fectious mononucleosis shares clinical features with active SLE, and results in antinu-
clear antibody (ANA) positivity and production of SLE-related autoantibodies such as
anti-Sm. One of the initial epitopes for autoantibody generation in SLE is thought to be
the 60-kDa antigen Ro, which is cross-reactive with EBV nuclear antigen 1 (EBNA1).6
The appearance of autoantibodies that cross-react with EBV proteins sometimes
several years before the onset of clinical symptoms is hypothesized to be due to
molecular mimicry of SLE-associated autoantigens (specifically anti-Sm and anti-Ro).
Although EBV exposure is highly prevalent in the adult population, patients with both
pediatric and adult-onset SLE are more likely to have molecular and antibody markers
of EBV.40,41 A meta-analysis of 25 case-control studies by Hanlon and colleagues42
evaluated the prevalence of serum anti-EBV antibodies among patients with SLE
and matched controls. Although publication bias could not be excluded, a significantly
higher prevalence of anti–viral capsid antigen (VCA) immunoglobulin (Ig)G positivity
(OR 2.08, 95% CI 1.15–3.76) but not anti-EBNA1 (OR 1.45, 95% CI 0.7–2.98) was
found in SLE cases when compared with controls. Anti–early antigen (EA)/D IgG
and anti-VCA IgA were also significantly higher among patients than in controls (OR
4.5 [95% CI 3.00–11.06] and OR 5.05 [95% CI 1.95–13.13], respectively).42
Differences in immunologic responses to EBV exposure being dependent on the
genetic background of the exposed individual serve as another example of gene-
environment interaction. Several SLE susceptibility genes play a role in EBV replication
and immune evasion,43 with an individual’s immune response to EBV infection being a
significant factor in the development of early autoantibodies.
INFLUENCE OF VITAMIN D STATUS ON SLE
Vitamin D, an essential steroid hormone with well-established effects on mineral meta-

bolism and skeletal health, also has important effects on the immune system.44 A high
prevalence of vitamin D insufficiency has been found in SLE patient populations
around the world, particularly among those with darker skin pigment, and observa-
tional studies suggest that insufficiency contributes to multiple comorbid conditions
and potential complications of SLE. It is notable that the same ethnic disparities
406 Kamen
seen in the prevalence of vitamin D deficiency are seen in the prevalence of SLE, with
African Americans and Hispanics having a disproportionately high risk for developing
SLE and having severe disease manifestations.
Cohort studies have examined potential links between vitamin D status and SLE dis-
ease activity, with disease features with the largest studies to date showing a signifi-
cant correlation between higher disease activity and lower 25(OH)D.45–49 Case-control
studies comparing levels of 25(OH)D are confounded by SLE patients avoiding sun
exposure because of photosensitivity, even when using an inception cohort of
patients.50
To address the question of whether vitamin D status influences the development of
SLE, it is important to assess reliable preclinical markers of disease. Ritterhouse and
colleagues48 demonstrated among healthy controls that vitamin D deficiency was
associated with autoimmunity (ANA positivity) and altered T- and B-cell responses,51
consistent with low levels of 25(OH)D being a potential risk factor in the pathogenesis
of SLE. Although causality remains to be determined, studies to date suggest a
possible role for vitamin D in the pathogenesis of SLE.
LESS ESTABLISHED ENVIRONMENTAL RISK FACTORS

Metals and SLE
Although experimental studies in rodent models suggest that metals may play a caus-
ative role in SLE, the epidemiologic data are currently lacking. Metals such as mercury
have been associated with ANA and inflammatory cytokine production in some
exposed individuals.52 The one published study to date of occupational and avoca-
tional metal exposures in SLE patients compared with controls found that exposure
to mercury in the occupational setting at least once per week was associated with a
modestly (but not significantly) higher risk of SLE (OR 3.1, 95% CI 0.8–12.7).28 Expo-
sure to 5 or more days of stained or leaded glass as a hobby was also more common
among SLE cases than in controls, but the rarity of these exposures led to an imprecise
effect estimate (OR 3.0, 95% CI 0.8–11.6).28 More studies are needed to determine if,
and in whom, exposure to certain metals influences the risk and/or course of SLE.
Pesticides, Persistent Organic Pollutants, and SLE

Exposure to pesticides has been a suspected risk factor for SLE, based on a higher
risk of disease reported among farmers and accelerated disease in pesticide-
treated lupus-prone mice.53,54 However, based on current published data there is
insufficient evidence to suggest that exposure to pesticides plays a causative role in
the development or progression of human SLE.
A history of mixing pesticides for agricultural work was associated with develop-
ment of SLE (although only 8% of SLE patients and 1% of controls reported the expo-
sure), but pesticide application was not associated with SLE in the same study.55 In an
analysis of the Women’s Health Initiative cohort, 50- to 79-year-old women who re-
ported personally mixing/applying insecticides (mostly in a residential setting) had
higher risks of developing SLE during the study follow-up, with trends of increasing
risk by frequency and duration of use.56 A history of living on a farm was also associ-
ated with a higher risk of developing SLE.56
Persistent organic pollutants (POPs) are halogenated organic compounds that are
resistant to environmental degradation through chemical, biological, or photolytic pro-
cesses. POPs include broad classes of compounds, such as organochlorine pesti-
cides (and pesticide metabolites), polychlorinated biphenyls (PCBs), dioxins, and
furans. Many are considered contaminants of emerging concern as these chemicals
with potential adverse health effects are becoming more common in the environment,
with increasing levels being found in humans.57
There have been few epidemiologic studies of POPs in relation to SLE. One study of
United States electrical workers (typically exposed to PCBs) reported 30% signifi-
cantly more mortality from musculoskeletal system diseases (ICD-9 codes 710–739)
and 40% more mortality from ICD-9 codes 710 to 725, classifications that include
the ICD-9 code for SLE.58 One cohort study with 24 years of follow-up in a Taiwanese
population that was accidentally exposed to high levels of PCBs and furans through
consumption of contaminated rice found higher mortality from SLE, with PCB-
related deaths starting 10 years after the exposure.59 An ongoing study of environ-
mental triggers of SLE among Gullah African Americans found ANA-positive controls
(48% at baseline) to have higher mean levels compared with ANA-negative controls
for perfluorooctanesulfonic acid (PFOS) (75.1 vs 48.2 ng/mL, P 5 .06), perfluoroocta-
noic acid (PFOA) (7.0 vs 5.8, P not significant), and perfluorononanoic acid (PFNA) (3.2
vs 2.1, P 5 .04).60 Serum PFOS and PFNA (P 5 .02 and .03) directly correlated with
annual servings of seafood and 40% of consumed local species known to contain
high levels of POPs. Although it is possible that POPs increase the risk of SLE,
more studies investigating the association are needed.
Other Environmental Agents and SLE

Other exposures worth investigating, but with currently few data on SLE associations,
include asbestos, industrial chemicals and solvents, personal care products (eg, cos-
metics), ultraviolet (UV) radiation, and air pollution. For example, case-control studies
performed in Boston,27 Canada,28 and the Carolinas55 included questions about past
exposure to solvents, but found mixed results and overall a low prevalence of expo-
sure to many of the specific solvents examined. A meta-analysis, which included those
same 3 studies of SLE, found a significant association between organic solvent expo-
sure and development of disease when multiple autoimmune diseases were com-
bined as the outcome (OR 1.54, 95% CI 1.25–1.92).61 There is also a paucity of
research on immune health risks associated with relatively widespread synthetic
chemical exposures, such as plasticizers (eg, phthalates and bisphenol A), which
can act as endocrine or immune disruptors. More research is needed on these and
other industrial chemicals in consumer products to determine whether they may
play a role in the development of SLE.
The only exposure deemed by the NIEHS Panel to be “unlikely” to contribute to
autoimmune disease was the use of hair dyes and development of SLE, for which
multiple case-control studies have not found an association.25
This lack of confident associations in either direction calls attention to the difficulties
inherent in investigating environmental risk factors. Progress is limited by multiple bar-
riers including, but not limited to: difficulty obtaining high-quality exposure data and
timing of exposure; lack of consistent and validated assessment tools; difficulty
defining which of multiple simultaneous exposures contributes to disease; and inade-
quate interdisciplinary training and collaboration between clinicians, epidemiologists,
and environmental scientists. In addition, clinicians lack clear definitions of suscepti-
bility windows related to age, developmental state, and hormonal changes, which
would help inform the timing of exposures and latencies of their effects.
METHODOLOGICAL LIMITATIONS IN STUDIES OF ENVIRONMENTAL INFLUENCES
Although increasingly sensitive and specific biomarkers of exposure and disease

continue to be discovered and used, most environmental risk studies to date rely on
408 Kamen
questionnaires to ascertain exposure and/or outcomes of interest. Cohort studies that

are used to make determinations about environmental risk factors often include ques-
tionnaires and other assessments not built to formally assess SLE or other autoimmune
diseases. If SLE is not one of the primary conditions under study, there is a greater
chance of misclassification of disease outcome. The current methods of capturing envi-
ronmental exposure are also limited by an excessively long lag time between time of
exposure of interest and time of assessment, which is particularly problematic in light
of SLE having a long preclinical phase and in today’s rapidly changing environment.
Defining the SLE Exposome

The concept of the exposome encompasses the complex interplay between an indi-
vidual’s exposures and his or her genome and epigenome, which result in an impact
on that individual’s health.11 Study of the exposome, or exposomics, relies on the
measurement of both internal and external exposures. Measurement of internal expo-
sures (eg, hormones, inflammation, oxidative stress, gut microbiota) involves the use
of biomarkers of endogenous processes. Measurement of external exposures (eg,
chemicals, infectious agents, UV radiation, diet, tobacco, medications) involves the
use of direct measurements and survey instruments to capture environmental and life-
style factors.
The question arises as to how to find the environmental risk factors for the large pro-
portion of SLE that remains unexplained by currently known genetic and environ-
mental influences. Determining the risk (and protective) factors for SLE will continue
to be highly challenging using traditional epidemiologic approaches whereby expo-
sures are gleaned from self-reported questionnaires. To help overcome these limita-
tions, a hypothesis-free exposomic approach is needed. This approach focuses on
the internal chemical environment arising from exposures, and includes internally
generated biomarkers of exposure to assist in defining exposure-response relation-
ships.62 Progress is being made in identifying and validating new exposure biomarkers
that can be used in population-based studies of diseases such as SLE, many of which
are supported as part of the Genes, Environment and Health Initiative and the Gene
Environment Association Studies consortium.63
FUTURE CONSIDERATIONS AND SUMMARY
Despite a tremendous amount of progress in elucidating potential environmental risk

factors of SLE, much more needs to be done. An interdisciplinary approach to studies
of the causes and, ultimately, the prevention of SLE is needed. Increasing dialogue
and collaboration between epidemiologists, biostatisticians, bioinformatics experts,
laboratory and environmental scientists, and lupus clinical researchers (lupologists)
will advance our collective contributions to an understanding of the causes of SLE.
Ultimately these collaborations will improve the assessment of environmental expo-
sure, enable evaluation of risk within biomarker-defined subgroups (eg, genetic poly-
morphisms or autoantibody status), and aid the discovery of diagnostic and
prognostic biomarkers.
A better understanding of the environmental risk factors for SLE will allow the design
of preventive measures based on well-informed predictive risk models. Ultimately, the
goal is to improve the quality of multidisciplinary research on the human health effects
of environmental exposures, and develop effective strategies for exposure reduction
and the prevention of autoimmune disease.
Important discoveries are being made regarding the pathways that allow envi-
ronmental stresses to influence an individual’s expression of autoimmunity and
autoimmune disease. For example, there is now ample evidence that the epigenome is
dynamic and changes in response to environmental exposures, including diet. This
finding has important implications for prevention as our understanding grows of
how epigenetic regulation of DNA is influenced by modifiable environmental and
dietary exposures, and how these variations play a role in the development of SLE
disease.
There is urgency in undertaking this quest for understanding SLE etiology, attribut-
able in part to the rising incidence of SLE, with more than 16,000 new cases diagnosed
annually in the United States alone. Also important is the potential for what is learned
about SLE etiology to benefit other autoimmune diseases, and the likelihood that
many other health conditions result from similar exposures.
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Clinical Perspectives on
Lupus Genetics
Advances and Opportunities
a,b,
Judith A. James, MD, PhD *
KEYWORDS
SLE Lupus Genetics Clinical subphenotypes GWAS Nephritis
Autoantibodies
KEY POINTS
Polymorphisms in genes important for ubiquitination, DNA degradation, innate immunity,
cellular immunity, antigen presentation, and lymphocyte development are associated and
confirmed in systemic lupus erythematosus (SLE).
Select genetic associations are enriched in patients with SLE with certain autoantibodies,
antiphospholipid syndrome, pericarditis, thrombosis, arthritis, or lupus nephritis.
New lupus genetic studies are warranted, especially with large cohorts enriched for under-
studied races, and in patients with severe disease or poor prognosis.
New lupus genetic studies are also warranted in large cohorts of patients with SLE with
phenotype information about common lupus comorbidities and response to therapeutics.
INTRODUCTION
Systemic lupus erythematosus (SLE; lupus) is a complex clinical syndrome with a wide
range of clinical symptoms and significant immune dysregulation including production
of high concentrations of autoantibodies. Lupus cases have been found to cluster in
families with 66% heritability and a lambda S between 8 and 29. Monozygotic twin
studies have shown 24% to 69% twin concordance rates, compared with the dizy-
gotic twin or sibling rates of 2% to 5%.1–3 Since the first genome-wide association
studies (GWAS) conducted in SLE were published in 2008,4–6 the number of associ-
ated and confirmed genetic associations has increased greatly, as shown and refer-
enced in Table 1, which summarizes these findings to December 2013.
Conflict of Interest: The author declares no conflict of interest.

a
Oklahoma Clinical & Translational Science Institute, University of Oklahoma Health Sciences
Center, 920 Stanton L Young Boulevard, Oklahoma City, OK 73104, USA; b Departments of
Medicine, Pathology, Microbiology & Immunology, University of Oklahoma Health Sciences
Center, 920 Stanton L Young Boulevard, Oklahoma City, OK 73104, USA
* Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation,
825 Northeast 13th Street, Oklahoma City, OK 73104.
E-mail address: judith-james@omrf.org

414 James
Pathways Implicated by Lupus Genetics

Genetic studies suggest, and mechanistic SLE studies support, the role of several
different processes being implicated in lupus pathogenesis, such as altered cell
signaling, impaired clearance of debris, and dysregulated immune cell develop-
ment, function, and response.3,7–9 Several of these pathways are discussed briefly
in this article and in Table 1. Please see the reviews in Refs.3,10–13 for additional
information.
Ubiquitination (nuclear factor kappa beta signaling)

Polymorphisms within several genes involved in ubiquitination (a process of marking
proteins for degradation) have been associated with SLE. Mutations in TNFAIP3
(tumor necrosis factor alpha-induced protein 3) can alter ubiquitin patterns, resulting
in improper degradation targeting and termination of proinflammatory responses
through nuclear factor kappa beta (NFkB) signaling.14 Mutations in TNIP1 (transition
protein-1), an adaptor protein whose expression is induced by NFkB,3 can result in
NFkB signaling pathway dysregulation.15 UBE2L3, ubiquitin-conjugating enzyme E2
L3 is a ubiquitin-carrier enzyme, is expressed on all lymphocytes and is important for
the ubiquitination of a NFkB precursor and cell development.3,8 IRAK1 (interleukin-1
receptor-associated kinase 1) encodes for a protein located downstream of NFkB
signaling and genetic mutations in this gene can offer protection from or susceptibil-
ity to SLE.8,16 Mutations in SLC15A4 (solute carrier family 15 member 4), a peptide
transporter in NFkB signaling pathway, and PRKCB (protein kinase C beta), a protein
kinase involved in B-cell receptor–mediated NFkB activation, have also been impli-
cated in SLE development in susceptible individuals.8
DNA degradation (apoptosis/clearance of debris)

In healthy individuals, apoptosis, or programmed cell death, is used to remove dead or
dying cells into the surrounding environment without releasing the cellular compo-
nents. However, in an individual with SLE, this process is defective, resulting in
decreased removal and, thus, accumulation of apoptotic cells, release of apoptotic
cellular materials into the surrounding environment, and activation of immune re-
sponses against self-antigens.3,7–9 Genetic studies have suggested that variants in
FcgRIIB (Fc gamma receptor II B), ITGAM (integrin alpha M), ATG5 (autophagy protein
5), ACP5 (acid phosphotase 5), TREX1 (three prime repair exonuclease 1), DNase 1,
and DNase 1L3 (DNase 1-like 3) may play a role in the development of lupus through
their roles in apoptosis or debris clearance.8,9,17–19 Dysfunction in any of these pro-
cesses leads to improper clearance of apoptotic cells and is associated with autoan-
tibody production and SLE pathogenesis.
Innate immunity (Toll-like receptor pathways/interferon)

A large number of individuals with SLE have increased expression of interferon (IFN)-
associated genes (IFN signatures) compared with healthy individuals. Because IFN
signaling is important in protection against viral infection and in the development,
activation, and proliferation of immune cells, dysregulation of IFN signaling pathways
can have major consequences regarding the morbidity and mortality of patients with
SLE. Genetic variants in Toll-like receptor (TLR) 7, TLR regulatory molecules
(UBE2L3), IFN signaling transcription factors (IRF5 [interferon regulatory factor 5],
IRF7/PHRF1 [interferon response factor 7/PHD and ring finger domains 1], IRF8
[interferon regulatory factor 8], ETS1) are associated with increased SLE susceptibil-
ity.8,9,20 Variants in molecules within or involved in the downstream signaling of the
IFN pathway, such as STAT4 (signal transducer and activator of transcription 4),
Table 1
Loci associated with SLE through GWAS, meta-analysis studies, candidate gene studies, or replication studies from 1992 to December 2013
Gene Pathway Location Variant Population References

94
IKBKE NFkB signaling 1q32.1 rs1539241/rs12142086 EU
4,15,23,77,95,96
TNIP1 Ubiquitination in NFkB signaling 5q32 rs10036748 EU, AA, AS
4,14,23,77,97–99
TNFAIP3 Ubiquitination in NFkB signaling 6q23 rs2230926 EU, AA, AS
15,23
SLC15A4 Ubiquitination in NFkB signaling 12q24.32 rs1385374 AS
100
UBASH3A Ubiquitination 21q22.3 rs9976767 EU
5,23,101,102
UBE2L3, HIC2 Ubiquitination in NFkB signaling 22q11.21 rs463426 EU, AS
4,77,103–105
IRAK1/MECP2 Ubiquitination in NFkB signaling Xq37 rs1734787 EU, HA, AS
106–110
Complement genes Apoptosis/clearance of debris; 1q36 Multiple EU
neutrophil/monocyte immunity
111,112
IL-2/IL-21 Apoptosis/clearance of debris; 4q26 rs907715 EU, AA, AS
4,5,23,77
ATG5 Apoptosis/clearance of debris 6q21 rs548234 EU, AS
4–6,77,103,113–115
ITGAM Apoptosis/clearance of debris 16p11.2 rs9888739 EU, HA, AS
Clinical Perspectives on Lupus Genetics

116,117
DNase 1 Apoptosis/clearance of debris 16p13.3 rs8176927 AS, A
118
ACP5/TRAP Apoptosis/clearance of debris 19p13.2 rs79525531 EU, AS, H
119,120
Mir146a mRNA stability/translation 6q5 rs57095329 EU, AA, AS
22
ZBP2 mRNA stability/translation 17q12 rs1453560 EU, AA
22
IFIH1 TLR/interferon pathways; T-cell immunity 2q24 rs1990760 EU
4,5,31,97,103,113,121–123
STAT4 TLR/interferon pathways; T-cell immunity 2q23.2 rs7582694 EU, HA, AA, AS
23
RASGRP3 TLR/interferon pathways 2p24.1 rs13385731 AS
77
PRDM1 TLR/interferon pathways; B-cell immunity; 6p21 rs6568431 EU
T-cell immunity
4,5,77,101,124–126
IRF5/TNPO3 TLR/interferon pathways 7q32 rs12537284 EU, HA, AA, AS
4,5,23,77
PHRF1/IRF7/KIAA1542 TLR/interferon pathways 11p15.5 rs4963128 EU, AA
(continued on next page)
415
416
James
Table 1
(continued )
Gene Pathway Location Variant Population References
22,127
IRF8 TLR/interferon pathways; neutrophil/ 16q24.1 rs116440334 EU
monocyte immunity
128,129
TLR7 TLR/interferon pathways Xp22.3 rs3853839 EU, AS
77
UHRF1BP1 Cellular growth 6p21 rs11755393 EU
130
TNXB Cellular adhesion 6p21.32–33 rs310342 AS
4,5,102,113
PXK Synaptic transmission 3p14.3 rs6445975 EU
97
HIP1 Endocytosis and protein trafficking 7q11 rs6964720 AS
4,77,111,131
NCF2 B-cell immunity 1q25 rs17849502 EU, AS
4,77,101,103,132
IL-10 B-cell immunity; lymphocyte activation; 1q31-q32 rs3024505 EU, AA, AS
4,103,133,134
BANK1 B-cell immunity 4q24 rs10513487 EU, HA, AA, AS
5,6,23,97,135,136
BLK B-cell immunity 8p3 rs7812879 EU, HA, AA, AS
5,137
LYN B-cell immunity 8q13 rs7829816 EU, AA, AS
138
ELF1 B-cell immunity; T-cell immunity 13q13 rs7329174 AS
139
PRKCB B-cell immunity 16p11.2 rs16972959 AS
22
IKZF3 B-cell immunity; T-cell immunity; lymphocyte 17q21 rs8079075 EU, HA, AA
development
140
CD40 B-cell immunity; antigen presentation 20q12 rs4810485 EU
5,77,101,141
PTPN22 T-cell immunity 1p13.2 rs2476601 EU, HA
4,5,23,77,102
TNFSF4 T-cell immunity 1q25 rs2205960 EU, HA, AS
97
AFF1 T-cell immunity 4q21 rs340630 AS
4,23,96
IKZF1 T-cell immunity; lymphocyte development 7p13 rs4917014 EU, AS
23,95–97,114
ETS1 T-cell immunity; B-cell immunity; TLR/ 11q24.3 rs6590330 AS
interferon pathways; lymphocyte
development
142
CSK T-cell immunity 15q24.1 rs3433034 EU
22,113
TYK2 T-cell immunity 19p13.2 rs280519 EU
143
SH2D1A T-cell immunity; B-cell immunity; lymphocyte Xq25 rs2049995 AS
development
144
CRP Neutrophil/monocyte immunity 1q21 rs3093061 EU, AA
4–6,15,23,39,43,77,
HLA genes Lymphocyte activation, antigen presentation 6p21.32–33 rs1270942 EU, HA, AA, AS
95,97,101,119,145,146
rs2647012
rs2187668
rs2301271
rs9271100
rs3135394
rs3131379
32
CD44, PDHX Lymphocyte activation 11p13 rs507230 EU, AA, AS
22
TMEM39A Unknown 3q13.33 rs1132200 EU, AS
147,148
TREX1 Unknown 3p21.31 rs3135945 EU
5
PITG1 Unknown 5q33.3 rs2431697 EU
4,77
JAZF1 Unknown 7p15.2 rs849142 EU
5,101
XKR6 Unknown 8p23.1 rs6985109 EU
Clinical Perspectives on Lupus Genetics

5
C8orf12 Unknown 8p23.1 rs7836059 EU
4,23,114,149
LRRC18, WDFY4 Unknown 10q11.23 rs1913517 AS
150
VKORC1 Unknown 16p11.2 rs9934438 AS
22,127
CLEC16A Unknown 16p13 rs12599402 AS
17q21 rs1453560 EU, AA
Abbreviations: A, Arab; AA, African American; AS, Asian; CLEC16A, C-type lectin domain family 16; CRP, C-reactive protein; CSK, c-src tyrosine kinase; c8orf12, chro-
mosome 8 open reading frame 12; ELF1, E74-like factor 1; EU, European; H, Hispanic; HA, Hispanic American; HIC2, hypermethylated in cancer 2; HLA, human
leukocyte antigen; HIP1, huntingtin interacting protein; IKBKE, inducible I Kappa-B Kinase; IKZF3, IKAROS family zinc finger protein 3; IL, interleukin; IRAK1, inter-
leukin-1 receptor-associated kinase 1; JAZF1, JAZF zinc finger 1; LRRC18, leucine rich repeat containing 18; MECP2, methyl CpG binding protein 2; MIR146A, micro-
RNA 146A; NCF2, neutrophil cyosolic factor 2; NFkB, nuclear factor kappa beta; PTPN22, protein tyrosine phosphatase, non-receptor type 22; PXK, PX domain
containing serine/threonine kinase; RASGRP3, RAS guanyl releasting protein 3; TLR, Toll-like receptor; TMEM39A, transmembrane protein 39A; TNXB, tenascin
XB; TRAP, triiodothyronine receptor auxiliary protein; TYK2, tyrosine kinase 2; UBASH3A, ubiquitin associated and SH3 domain containing A; UHRF1BP1,
UHRF1 binding protein 1; VKORC1, vitamin K epoxide reductase complex subunit 1; WDFY4, WDFY family member 4; XKR6, Kell blood group complex sub-
unit-related family member 6.
417
418 James
IFIH1 (interferon induced with helicase C domain 1), and PRDM1 (positive regulatory
domain containing 1, with ZNF domain), have also been associated with increased
susceptibility of SLE.8
B-cell immunity (function/signaling)

A hallmark of SLE is the presence of autoantibodies, which indicates improper
function and signaling of B cells. BLK (B lymphocyte tyrosine kinase), BANK1
(B-cell scaffold protein with ankyrin repeats 1), and LYN genetic variants increase
SLE susceptibility, perhaps through altering B-cell receptor signaling.8,9,21 IRF8,
ETS1, IKZF1 (IKAROS family zinc finger 1), AFF1 (AF4/FMR2 family member 1),
RasGRP3 (Ras guanyl releasing protein 3), PRDM1, FcgRIIB, PRKCB (protein
kinase C beta), and NCF2 (neutrophil cytosolic factor 2) are major players in the
development, differentiation, proliferation, and activation of B cells, and they also
contain polymorphisms associated with SLE susceptibility.8,9,22–24 Polymorphisms
in HLA-DR2 (human leukocyte antigen- DR2) and DR3 (alter ability to produce
antibodies), IL-10 (interleukin 10, inhibits T cells and antigen-presenting cells,
enhances B-cell survival and activity), and IL-21 (promotes antibody class switch-
ing and sustains autoantibody production) also contain associated and confirmed
polymorphisms with SLE.8,9
T-cell immunity (function/signaling)

T cells play a role in both innate and adaptive immune responses. In patients with SLE,
altered T cells play a role in the activation of autoreactive B cells, production of anti-
bodies, and the immune surveillance of regulatory cells. Mutations in ETS1, IKZF1,
PRDM1, AFF1, and TNFSF4 (tumor necrosis factor superfamily member 4) have
been associated with altered differentiation, activation, and proliferation of SLE
T cells.8,9,25–28 Dysregulated T-cell signaling has also been associated with PTPN22
(protein tyrosine phosphatase, non-receptor type 22), TYK2 (tyrosine kinase 2), and
STAT4 mutations in SLE.8,9,29–31 Genetic variations in HLA-DR2 and DR3, CD44,
IL-10, and IL-21 are associated with altered lymphocyte activation by T cells in pa-
tients with SLE.8,9,21,32
Neutrophil/monocyte immunity (function/signaling)

Neutrophils and macrophages are important players in the innate and adaptive im-
mune system. As a first line of defense, these cells migrate to areas of inflammation,
are involved in the removal of dead cells and foreign antigens, and directly affect the
activation of lymphocytes. ITGAM and ICAM (intercellular adhesion molecule) poly-
morphisms lead to altered migration and adhesion of the neutrophils and monocytes
in patients with SLE.8,9 Genetic variants in FcgRIIB and FcgIIIA/B (Fc gamma region
receptor IIIA/B), IL-10, and IRF8 can alter phagocytosis, monocyte signaling, and
macrophage development, drastically changing the innate immune responses of pa-
tients with SLE.8,9
Lymphocyte development
In individuals with autoimmune disorders, impaired lymphocyte development leads to
an increase in autoreactive lymphocytes, lymphocytes with altered tissue homing abil-
ity, and cells with inappropriate responses to external environmental stimuli. ETS1 and
IKZF1 both play a role in the regulation of lymphocyte differentiation and develop-
ment.33,34 Genetic variants of these genes result in abnormal differentiation of
B cells into plasma cells, increased proliferation of Th17 cells, and loss of regulation
of self-tolerance.35–38
Clinical Perspectives on Lupus Genetics 419
Antigen presentation
In order to make a robust immune response to protect the host, foreign antigens must
be taken up, processed, and presented to T and B cells. However, in individuals with
SLE, variations in the HLA-DRB1/MHC1 (major histocompatibility complex 1) genes
can lead to altered antigen presentation.5,39,40
Genetic Associations with Autoantibody Production

Despite the many variations of clinical presentation, almost all individuals with SLE
develop antibodies against self-antigens, particularly antinuclear antibodies against
double-stranded DNA (dsDNA), Ro, La, Sm, nRNP, ribosomal P, and antibodies
against phospholipids.
Polymorphisms within the human leukocyte antigen (HLA) genes are among the
best-known risk factors for the development of SLE. In addition to the increase of
overall SLE risk, these HLA polymorphisms are associated with increased risk of auto-
antibody development.41 HLA haplotypes consisting of DRB1*1501/DQB1*0602 (DR2)
are associated with anti-Sm responses, whereas HLA DRB1*0301/DQB1*0201 (DR3)
haplotypes are associated with anti-Ro and anti-La responses.41 Individuals with a
mixture of DR2/DR3 haplotypes have an increased prevalence of anti-Ro, anti-La,
and Sm antibodies.41
Additional genetic polymorphisms are likely important in autoantibody development.
Ramos and colleagues42 performed a linkage study for the presence of autoantibodies
in a large collection of families multiplex for SLE and found regions on chromosome
3q21 linked with anti-La, chromosomes 4q34 and 4q35 with anti-Ro and/or anti-La,
and chromosome 3q27 with anti-nRNP. Immunoglobulin M antiphospholipid antibody
responses were enriched in individuals at chromosome 13q14.42 Large-scale genetic
association studies of collections of patients with SLE and controls with autoantibody
detection by the same method, ideally at the same time, would be useful to help delin-
eate genes and pathways further involved in the genetic susceptibility to SLE.
Although only 40% to 60% of patients with lupus develop antibodies to dsDNA,43
anti-dsDNA responses are strongly associated with lupus nephritis and often indicate
a poor survival outcome.44,45 Chung and colleagues43 identified genetic variants in
STAT4, ITGAM, K1AA1542, BANK1, and UBE2L3 that associate with the presence
of anti-dsDNA antibodies in patients with SLE.
Several other genetic polymorphisms are associated with the presence of autoan-
tibodies in patients with lupus. In a Japanese SLE cohort, polymorphisms in PHRF1
are associated with the presence of anti-Sm antibodies.46 PTPN22 polymorphisms
are associated with the presence of anticardiolipin antibodies (a type of antiphospho-
lipid antibody) in European American and anti-nRNP antibodies in Hispanic patients
with SLE.47 An IRF8 variant is associated with the development of antibodies against
dsDNA across European American, African American, and Cretan patients with
lupus.48 This topic is further reviewed in Refs.49–51
Association of Genes Within Select Lupus Clinical Subsets

In recent years, an emphasis has been placed on identifying individuals at the greatest
risk of developing severe lupus to improve monitoring and identify individuals for
potential therapeutic clinical trials.
Studies have shown that the PTPN22 risk allele is enriched in patients with SLE with
antiphospholipid syndrome and in patients with concurrent autoimmune thyroid dis-
ease.47 TRAF3IP2 (TRAF3 interacting protein 2) polymorphisms are associated with
the development of pericarditis.52 Genetic variants in FGG (fibrinogen gamma chain),
MTHFR (methylenetetrahydrofolate reductase), and FVL (factor V Leiden) have been
420 James
shown to be associated with increased risk of thrombosis in European Americans,

whereas FGG is only associated with increased risk of thrombosis in Hispanic patients
with lupus.53 BANK1 variants are associated with hematological, immunologic, and
renal subphenotypes of SLE.54 A recent study by Sanchez and colleagues55 examined
the contribution of genetic risk alleles for SLE with clinical subphenotypes of the dis-
ease, and TNFSF4 polymorphisms were significantly associated with renal disorder in
individuals with European ancestry.55 Polymorphisms in ITGAM are associated with
arthritis56 and nephritis.57
Genetic polymorphisms that alter expression levels of the MIF (macrophage migra-
tion inhibitory factor) gene affect both the overall risk for developing SLE and subphe-
notype susceptibility. The high-expression MIF allele is associated with a lower risk of
SLE and lower risk of antinuclear antibody production. However, if the lower-
expression allele is present, and SLE develops, individuals then have an increased
risk of serositis, double the risk for nephritis, and a nearly 9-fold risk increase in cere-
britis.58 A more in-depth description of the genetic associations with clinical subphe-
notypes of SLE is given by Rullo and Tsao8 and later in this article.
Genetics of Nephritis and Renal Outcomes

One of the most serious clinical symptoms of SLE can be lupus nephritis (LN), espe-
cially when associated with end-stage renal disease. Although many studies have
identified genes associated with increased risk of developing SLE, genetic association
with LN or end-stage renal disease remains an understudied area. Polymorphisms in
several genes (Table 2) have been associated with increased risk of LN and vary
based on gender and race.16,59–61
ABIN1/TNIP1
ABIN1 (A20-binding inhibitor of NFkB) [D485N] transgenic mice develop an SLE-like
autoimmune disease,62 developing proliferative glomerulonephritis with histologic fea-
tures similar to class III and IV human LN.16 Single-nucleotide polymorphisms (SNPs)
within TNIP1, located within the ABIN1 gene, have previously been associated with the
development of SLE.63 Caster and colleagues16 examined the association of TNIP1
with LN in a large multiracial cohort (n 5 16,999), showing that SNP rs7708392 and
rs495881 in TNIP1 were significantly associated with LN in individuals with European
(P 5 3.66310 24) or African (P 5 8.47310 23) ancestry.16
Table 2
Genetic variants associated with LN
Gene Location Variant Population References

16,62,63
ABIN1/TNIP1 5q32 rs7708392 EU
rs495881 AA
64,65,67–71
APOL1 22q13.1 rs2157257 EU
rs5750250
rs2413396
rs4820232
rs73885319; rs60910145/rs71785313 AA
72,73
FcgRIIB 1q23 rs1050501 EU
74–76
STAT4 2q32.2–32.3 rs11889341 EU
rs7582694
10,23,77,78
TNFSF4 1q25 rs2205960 AS
rs10489265
APOL1
APOL1 (apolipoprotein L1 gene) polymorphisms have been associated with progres-
sive nondiabetic nephropathy in African Americans.64–70 Freedman and col-
leagues65,66 found that the G1 and G2 alleles of APOL1 are significantly associated
(P 5 6.2310 6) with the risk of developing LN end-stage renal disease in African
Americans (n 5 1389). However, a smaller study (n 5 407 African Americans) by Lin
and colleagues71 observed only a minimal association (P 5 .023) of APOL1 with LN
in African Americans individuals with SLE.
FcgRIIB
Fc gamma receptors (FcgR) play a large role in the clearance of immune complexes
and are major players in SLE pathogenesis. Impaired clearance and removal of im-
mune complexes may result in immune complex deposition in organs, which could
then lead to organ damage. GWAS have implicated FcgR polymorphisms as ge-
netic risk factors for SLE.72 However, these studies were in SLE as a whole and
did not assess the association of these receptors with clinical phenotypes.
A small study from Zidan and colleagues73 (n 5 90) identified the FcgRIIB 232
ILE/Thr polymorphism as increasing the risk of the development of LN in Egyptian
patients with SLE.
STAT4
STAT4 polymorphisms have been associated with several different autoimmune dis-
eases, including SLE. STAT4 polymorphisms have been associated with LN in individ-
uals of European descent and with severe LN.74,75 Bolin and colleagues76 used GWAS
to examine genetic association with LN in 2 Swedish cohorts, showing genome-wide
significant association (P<5 10 8) in 4 SNPs located within the STAT4 gene. In addi-
tion, STAT4 association was found in patients with SLE with severe renal insufficiency
(P 5 7.6 10 6).76
TNFSF4
Previous reports have linked TNFSF4 with susceptibility to SLE in Chinese and Euro-
pean individuals.10,23,77 Zhou and colleagues78 found a significant additive association
between TNFSF4 alleles rs2205960 (P 5 .014) and rs10489265 (P 5 .005) and LN.
SLE Genetic Studies in Progress

Despite all of the studies that have been performed to help decipher genetic contribu-
tions to lupus, many areas for further exploration remain. SLE is often more severe with
poorer outcomes in some racial subpopulations, including African American, Amer-
ican Indian, and some Asian subpopulations.79–83 However, to date, the major
GWAS have focused on individuals of European descent or select Asian populations,
but GWAS are currently underway in populations from additional racial demo-
graphics.84 These studies may identify genetic associations that are unique to select
populations and may also serve to help narrow associated regions by allowing trans-
racial mapping across common genetic areas of association.
Larger GWAS have already been published for other autoimmune diseases, such as
multiple sclerosis85 and rheumatoid arthritis.86 These studies, of greater than 72,000
subjects in each, have nearly doubled the number of confirmed genetic associations
for these complex human diseases with lower heritability compared with SLE. There-
fore, large SLE studies may help to identify additional confirmed genetic associations
that help to address the unexplained heritability in SLE. These findings may, in turn,
help focus or expand pathways important to lupus pathogenesis. Once causal variants
are identified and a greater amount of the genetic heritability of SLE has been
422 James
described, then another large opportunity will evolve to further explore gene-gene,
gene-environment, and other types of pathway analyses with SLE.
Studies are also ongoing to perform directed deep sequencing, exome se-
quencing, and whole-genome sequencing in patients with SLE compared with
healthy controls and family members to identify rare variants that are missed on
the GWAS arrays and may be important in lupus pathogenesis or within smaller ho-
mogenous subsets of this disease. With the decreasing cost of exome and whole-
genome sequencing, new data will likely accrue quickly, allowing broader studies
of rare variants.
Copy number variations (CNVs) are also beginning to be explored in lupus patho-
genesis. Yu and colleagues87 have shown that CNVs of interleukin (IL)-17F, IL-22,
and IL-21 are associated with SLE. Additional CNV studies are warranted to examine
other potential SLE genetic associations.
For many of these confirmed SLE genetic associations, functional consequences of
putative causal variants have yet to be elucidated. Novel methods and analytical ap-
proaches to help speed throughput, prioritize candidates, and select the highest likeli-
hood variants for functional impact and potential causation are needed to help make
the next breakthrough in deciphering the impact of genetic risk on lupus pathogenesis.
Although time consuming, these necessary next steps are crucial to help move toward
more directed therapies or better selections of patients for specific therapeutic
interventions.
FUTURE CONSIDERATIONS
Opportunities for Additional Clinically Important Genetic Studies
Although significant advances have been made in identifying and confirming genetic
associations in SLE, opportunities abound to move lupus genetic studies toward
even more clinically informative end points (Box 1).
Box 1
Opportunities for clinically important genetic studies
1. Markers of early damage or poor prognosis

2. Markers of persistently increased disease activity
3. Markers of severe disease
4. Expanded studies of genetic architecture of clinical subphenotypes
5. Larger sample size (to allow subsetting)
6. Opportunities to examine genetic associations with:
a. Atypical disease presentations
b. Uncommon clinical subtypes
c. Phenotypes enriched within select large multiplex families
7. Novel analytical methods
8. Markers of common SLE comorbidities
9. Pharmacogenetics
a. Markers of early flare off medication
b. Selection of medication
c. Response to medication
Many lupus consortia are performing studies to help identify early in the course of
disease the patients at the highest risk of damage or early mortality. For example,
work from the University of Toronto Lupus Clinic has shown that 25% of patients
with SLE with early damage (defined as Systemic Lupus International Collaborating
Clinics [SLICC]/American College of Rheumatology [ACR] Damage Index [SDI] score
1 at initial assessment) died within 10 years of their initial assessment compared with
only 7.3% without early damage (log rank P 5 .0002).88 Work from the LUMINA (Lupus
in Minority Populations, Nature versus Nurture) consortia assessed 5-year follow-up
data from 288 patients to identify potential predictors of early mortality. Living below
the poverty level (odds ratio [OR], 4.06; confidence interval [CI], 1.50–11.01), SDI at
initial visit (as discussed earlier) (OR, 1.45; CI, 119–1.91) and a disease activity mea-
sure at baseline (SLAM [Systemic Lupus Activity Measure]; OR, 1.09; CI, 1.01–1.17)
were each associated with early mortality in 34 individuals who died during the first
5 years of study.89 If lupus cohorts of sufficient size and with SDI measurements
near lupus onset can be assembled, assessing the genetic risk of those patients
with SLE at increased risk of early mortality and/or increased morbidity would be
useful in guiding therapeutic selection and potential pathway-directed therapies.
As an alternative, some patients with SLE followed in longitudinal cohorts have
persistently increased disease activity and therefore may have increased risk of dis-
ease damage as measured by SDI.90 Genetic analysis of these patients may be useful
in better understanding patients who are candidates for more aggressive immunosup-
pression or, conversely, better understanding the genetic susceptibility of patients
with persistently quiescent or suppressed disease may help lead to pathways that
may help temper or control lupus inflammation and damage.
Definitions of severe lupus have been difficult to adapt and are usually focused on
specific individual clinical manifestations of lupus, such as nephritis or major central
nervous system involvement. Alternate approaches have explored the total number
of ACR classification criteria.91,92 Another approach that may be useful is to use ther-
apeutic use as a surrogate for severe disease. Most rheumatologists and other lupus
care providers do not give major immunosuppressive drugs, such as cyclophospha-
mide, cyclosporine, or rituximab, to patients with mild or moderate lupus. Although pa-
tients with nephritis might dominate this category, patients with other less common
serious manifestations of lupus, such as cerebritis, systemic vasculitis, or pulmonary
hemorrhage, would not be eliminated from this analysis. As the field evolves and it
becomes easier to clinically define those patients with the most severe forms of
SLE, genetic, as well as partnered genomic, epigenetic, and immunologic measure-
ments may help provide critical insights to the most appropriate pathways to target
in these highest-risk individuals.
Many opportunities remain in further assessing the genetic architecture of SLE clin-
ical subphenotypes. Expansion of sample sizes of the lupus phenotype genetic asso-
ciation studies, as well as detailed clinical phenotypes for ACR classification criteria
and subcriteria are needed. Detailed phenotype data might also provide opportunities
to look for genetic associations with atypical presentations, such as antinuclear anti-
body negative, or uncommon clinical subtypes, such as thrombocytopenia at diag-
nosis, that are enriched within select large multiplex families or are found often
enough to be studied in large case-control association studies. Novel analytical
methods that allow for more sophisticated bioinformatic assessments of clinical
subgroups are also intriguing options to provide more insight to clinical subtypes iden-
tified by machine learning or other methods (see review by Bentham and Vyse93).
Alternate options for further genetic dissection would allow testing of markers of
genetic risk with comorbidities that are enriched in patients with lupus, such as
424 James
accelerated atherosclerosis and osteonecrosis. Genetic associations of response to

therapy would help with selection of medications, optimization of treatment, or poten-
tially identification of individuals at increased risk of select toxicities.
ACKNOWLEDGMENTS
The author thanks Jennifer Kelly and Julie M. Robertson, PhD, for the scientific edit-
ing of this article.
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Impact of Race and
Ethnicity in the Course and
Outcome of Systemic Lupus
Erythematosus
Luis Alonso González, MDa, Sergio M.A. Toloza, MD
b
,
Graciela S. Alarcón, MD, MPH, MACRc,*
KEYWORDS
Systemic lupus erythematosus Ethnicity Disparities Disease activity Damage
Mortality Treatment Kidney replacement therapy
KEY POINTS
No homogeneous racial groups exist within the human race.
Ethnicity is a biological and social construct.
Ethnic and regional differences influence the incidence, prevalence, expression, response
to therapy, and prognosis of patients with systemic lupus erythematosus (SLE).
Less favorable outcomes are experienced, overall, by nonwhite patients with SLE.
INTRODUCTION
Ethnicity is a biological and a social construct, which includes ancestral genes and
cultural, geographic, and socioeconomic characteristics shared by populations.1,2
In contrast, race refers to genetically homogeneous groups of people, which is hardly
the case for the human race.3 The US population is heterogeneous even within its
ethnic groups, as shown when ancestry informative markers (AIMs, genetic markers
differentially expressed in founding populations) were examined in the LUMINA (Lupus
in Minorities: Nature vs Nurture) study; in Texan Hispanic patients (mostly of Mexican
origin) nearly half of their AIMs were Amerindian (48%); in contrast, the Puerto Rican
Disclosure: None.
a
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Universidad
de Antioquia, Calle 70 N 52-21, Medellı́n, Antioquia 229, Colombia; b Department of
Medicine, Rheumatology Unit, Hospital San Juan Bautista, Avenida Illia 200, San Fernando
del Valle de Catamarca, Catamarca 4700, Argentina; c Division of Clinical Immunology and
Rheumatology, Department of Medicine, School of Medicine, The University of Alabama at
Birmingham, 510 20 Street South, FOT 830, Birmingham, AL 35294, USA
* Corresponding author.
E-mail address: galarcon@uab.edu

434 González et al
Hispanics had a larger proportion of white/European (35%) and African AIMs (45%);
whites and African Americans had about 20% of AIMs of the opposite group.4,5 The
term Hispanic (in the United States) applies to all individuals whose origin can be
traced to a Spanish-speaking country, and it is a very heterogeneous population
group. On the other hand, approximately 40% of Latin Americans are mestizos, or
of mixed European and Amerindian ancestry, but there is great variability within the
individual countries. The remaining Latin Americans are of European, African, or Asian
ancestry; despite this heterogeneity, in the United States, these individuals may be
grouped with the Hispanics, although some distinctions may be made (such as
Hispanic blacks).6 It has been shown that there is a tight association between race/
ethnicity (race is used in this review if used in the publication being cited) and socio-
economic features, with minorities having a lower socioeconomic status (SES) than
the white majority.5,7,8 Thus, differences in disease expression, intermediate-term
(disease activity), mediate-term (damage accrual, work disability, health-related qual-
ity of life), and long-term (mortality) outcomes relate to both components of ethnicity,
and it is difficult to disentangle the influence of each one.
In the following sections, the influence of race and ethnicity on disease expression,
disease outcomes, response to therapy, and renal replacement therapy is discussed.
DISEASE EXPRESSION
Differences in disease expression, including disease activity and damage accrual, as a

function of ethnicity have been well documented (Table 1).1,9–12 In general, patients
from ethnic minorities not only develop systemic lupus erythematosus (SLE) more
frequently, but tend to have an acute disease onset, present a greater number of,
and more severe, clinical manifestations, show higher disease activity, have a higher
risk of relapses, accrue more damage (and at a faster pace), and show higher mortality
than whites.6,7,13–18 SLE also tends to present at a younger age in nonwhites
(Hispanics, African descendants, and Asians).6,13,18–20
Distinct clinical SLE patterns are found among patients from different ethnic groups.
Whites, for example, show cutaneous manifestations more frequently, particularly,
photosensitivity and malar rash.15,20,21 In contrast, African descendants experience
discoid lupus more frequently,10,15,21 except for the Gullah population of the Sea
Islands of South Carolina, African descendants with minimal genetic admixture, and
in whom most integument manifestations are described.22 Hispanics, African descen-
dants, and Asians show renal, hematologic, serosal, neuropsychiatric, and immuno-
logic manifestations more frequently than whites.8,13,15,23–26 Lupus nephritis (LN),
the most worrisome SLE manifestation, is significantly more prevalent in mestizos,
Hispanics, Africans, and Asians.8–10,21,24–33 For example, in the LUMINA cohort, LN
occurred more frequently and tended to occur earlier in the African Americans
(62%) and Texan Hispanics (62%), whereas in the Puerto Rican Hispanics, LN
occurred at a rate comparable with the whites (26%).13,28,34 When the contribution
of admixture, preferentially reflecting the genetic component of ethnicity, and SES
to renal involvement was examined in these patients, admixture explained a larger
proportion (African primary but also Amerindian) of the ethnicity-dependent variance
than SES (36.8% vs 14.5%), whereas both accounted for an additional 12.2% of
the variance.5 Sánchez and colleagues35 showed in a larger study that Amerindian
ancestry is a predisposing factor for LN occurrence, whereas Richman and col-
leagues26 reported that European ancestral genes are protective.
In the GLADEL (for Grupo Latinoamericano de Estudio del Lupus or Latin American
Group for the Study of Lupus) cohort, the African Latin American patients and the
Race and Ethnicity in SLE 435
mestizo patients tended to develop renal disease more frequently and earlier than the
whites, and this was statistically significant only for the mestizo patients.10,32,36
Contreras and colleagues8 in a study conducted in South Florida in which 213
biopsy-proven cases of LN in patients from 3 different ethnic groups (whites,
Hispanics, and African Americans) were included, found less favorable outcomes in
the African Americans and Hispanics. Renal events (doubling serum creatinine level
or end-stage renal disease [ESRD]) or death occurred with a frequency 3 times higher
in African Americans and 2 times higher in Hispanics when compared with whites. The
Hispanics included in this study were predominantly Cuban and South American.
We have observed differences in disease expression in the 2 Hispanic subpopula-
tions we have studied. The Texan Hispanics tend to have a more severe disease than
the Puerto Rican Hispanics, as shown by higher levels of disease activity, more dam-
age accrual, and more frequent occurrence of LN, psychosis, serositis, and thrombo-
cytopenia. In turn, the Puerto Rican Hispanics tend to have integument manifestations
such as photosensitivity, malar rash, and discoid lupus more frequently.37 The Texan
Hispanics have a disease as severe as that of African Americans.13,18,38 The US
Hispanics, particularly those of Amerindian ancestry, tend to also develop obesity,
diabetes, hypertension, and the metabolic syndrome more frequently than do the
non-Hispanic whites,6,39,40 which has also been proved to be the case in Hispanics
from Mexico, as described in cross-sectional analyses of the SLICC (Systemic Lupus
International Collaborating Clinics) inception cohort.41 In this study, Korean patients
also showed the metabolic syndrome frequently although central obesity occurred
less commonly than in the Hispanics.
Asian patients with lupus also experience a more severe disease than whites, with
higher rates of neuropsychiatric involvement,24,25 but comparable with those reported
in Afro-Caribbean patients.21 Asian patients with lupus also develop LN at rates com-
parable with that observed among Afro-Caribbean, African American, and Texan
Hispanic patients (58%–69%).20,21,24,25,29,31 Compared with whites, the risk of renal
disease in Asian patients is, overall, 3 times higher,20 but there is significant variability
among various Asian populations; higher rates are observed among Chinese (57%),
Indians in Malaysia (70%), and Malaysians (70%–76%), but not in Pakistanis
(33%).11,12,42,43 Indian patients in Malaysia also experience neuropsychiatric involve-
ment frequently (36%–39%).11,42 In agreement with these findings, Asian patients with
lupus in Canada and the United Kingdom experience significantly more renal involve-
ment than whites21,31,33; however, like in Asia, the prevalence rates are not uniform,
with higher prevalence observed in Chinese patients (100.3 per 100,000 population)
than in patients from the Indian subcontinent (21.4 per 100,000 population).31
DISEASE ACTIVITY
Disease activity either at disease onset or over the duration of the disease, regard-
less of how it is measured, has been found to be higher among nonwhites (African
Americans, Afro-Caribbeans, African Latin Americans, Texan Hispanics in the United
States, mestizos in Latin America, and Asians in Australia), although the differences
have not always been statistically significant.7,10,17,20,36,44–47 At disease onset, there
seems to be an important genetic contribution to disease activity, but over the
course of the disease, socioeconomic features seem to exert a more important
role, as shown in the LUMINA study.44,45
As in the LUMINA study, in the SLICC cohort,46 whites had significantly lower dis-
ease activity at each yearly assessment over a 5-year follow-up period compared
with nonwhites, with the difference in disease activity mainly driven by Asians and
436
Table 1
Cumulative clinical features of SLE in different ethnic groups
Cervera
et al,9 2003 González, Alarcón et al,1 2013 Pons-Estel et al,10 2004 Mok et al,12
Euro-Lupus LUMINA Cohort GLADEL Cohort Wang et al,11 1997 2008
Geographic area Europe United States Latin America Malaysia Hong Kong
White (97%) Hispanic African-
African African Latin
descent (2%) Texas Puerto Rico American White Mestizo American White Chinese Malaysian Indian Chinese
Ethnic group (n 5 1000) (n 5 118) (n 5 102) (n 5 239) (n 5 181) (n 5 537) (n 5 152) (n 5 507) (n 5 412) (n 5 92) (n 5 35) (n 5 442)
Gender, women (%) 90.8 93.2 95.1 89.5 85.1 89 89.5 90.7 92.6 overall 91
Mean age at 31 (13) 31.4 (12.1) 35.1 (11.2) 33.1 (11.1) 39.8 (13.9) 29.9 (12.5) 26.9 (10.8) 31.1 (12.5) 25.9 (10.5) 24.2 (9.4) 23.9 (6.9) 32.3 (14)
diagnosis/onset
(y) (SD)
American College of Rheumatology criteria (%)
Malar rash 31.1 58.5 79.4 53.1 75.1 59 63.2 63.3 64.8 57.3 21.1 55
Discoid rash 7.8 4.2 11.8 33.9 9.4 10.4 19.7 11.2 4.5 9.3 9.1 9
Photosensitivity 22.9 55.9 90.2 56.1 81.2 51.8 59.2 59.8 45.1 35.4 12.1 30
Mucosal ulcers 12.5 61.0 48.0 55.7 76.2 43.2 40.1 40.6 33.1 37.5 45.4 17
Arthritis 48.1 86.4 73.5 82.4 85.8 92.5 94.1 93.5 49.8 52.1 57.6 77
Serositis 16 67.0 19.6 66.1 40.9 — — — 19.5 22.9 18.2 19
Renal disorder 27.9 55.1 28.4 58.2 17.1 58.3 55.3 43.6 75.8 66.7 69.7 57
27.7a 21.7a 26.4a
Neurologic disorder 19.4 14.4 3.9 19.7 8.3 22.5 20.8 36.4 13
Hematologic — 86.4 76.5 87.9 72.9 74.3 80.3 68.2 82.9 75 81.1 —
disorder
Thrombocytopenia 13.4 33.5 5.9 25.1 17.7 18.2 23 19.1 31.2 23 36.4 28
Hemolytic anemia 4.8 11.9 2.9 15.9 7.7 11.5 9.9 13 13.1 17.7 24.2 24
Positive ANA 96 100 96.1 98.7 99.5 95.9 99.3 99.4 92.7 92.7 93.9 —
Anti-dsDNA 78 77.1 52.0 62.8 40.9 74.6 69.5 67.2 69.9 57.3 72.2 71
Anti-Sm 10 33.1 21.6 54.4 26 48.8 50.0 47.1 — — — 15
IgG/IgM 24/13 — — — — 48.7/42.6 41.4/27.5 55.0/41.4 — — — 29b
anticardiolipins
Lupus 15 2.5 2.0 5.4 3.9 24.7 8.3 38.1 — — —
anticoagulant
Abbreviation: ANA, antinuclear antibodies; anti-dsDNA, anti-double-stranded DNA antibodies; SD, standard deviation.
a
Besides the American College of Rheumatology criteria (psychosis, seizures), other neurologic manifestations included are chorea, organic brain syndrome, transverse myelitis,
stroke, cranial nerve disease, polyneuritis, mononeuritis multiplex, or lupus headache.
b
Overall antiphospholipid antibodies.
Adapted from González LA, Toloza SM, McGwin Jr G, et al. Ethnicity in systemic lupus erythematosus (SLE): its influence on susceptibility and outcomes. Lupus 2013;22(12):1216; with
permission.
437
Hispanics. Golder and colleagues,20 in a single-center study conducted in Australia,

found that Asian patients have a disease significantly more severe with higher time-
adjusted mean Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
scores, higher maximum SLEDAI score, and more frequently persistent disease activ-
ity compared with non-Asians (most of them whites). Furthermore, Asians were more
likely to have persistently active disease, as defined when patients had at least 2
consecutive visits with an SLEDAI score of 6 or greater. Similar data have not emerged
from Asian countries.
DAMAGE ACCRUAL
Damage or the irreversible consequences of the disease or of the therapies used to

abate its manifestations has been extensively studied. The SLICC Damage Index
(SDI) documents irreversible organ system manifestations present for at least 6 months
from disease onset.48 Factors associated with damage occurrence include older age,
male gender, African American and Texan Hispanic ethnicities, poverty, disease dura-
tion, disease activity, number of American College of Rheumatology criteria met, gluco-
corticoid use, and abnormal illness-related behaviors.13,18,21,49–53 In addition, Texan
Hispanics accrue damage more rapidly than patients from the other ethnic groups.18,54
When these patients were compared with patients from Northern Spain (Spaniards),
SDI scores were comparable at baseline, but at year 4, their scores were higher, despite
having shorter disease duration at enrollment than the Spaniards.51 Previous damage
has been found to be a risk factor for the occurrence of further damage.55–58 It seems
that the combination of a more severe disease and poor SES acts synergistically,
contributing to greater damage accrual among minorities in the United States and
elsewhere.13
Differences in the pattern of organ damage have also been observed. For example,
neuropsychiatric damage occurs more frequently among whites, as described in the
Maryland and LUMINA cohorts.59,60 Renal damage occurs more frequently among
African Americans, Afro-Caribbeans, and Texan Hispanics, as documented in several
studies15,28,61; however, in the CLU (Carolina Lupus) study,49 the association of renal
damage and nonwhite ethnicity was no longer significant after adjusting for age and
household income, further reinforcing the role of SES in damage accrual in lupus.
Furthermore, Texan Hispanics and African Americans tend to develop ESRD more
frequently than patients from other ethnic groups.28,62–64 In African Americans, genetic
factors have been shown to contribute to the risk of LN-ESRD; the apolipoprotein L1
gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare
in European Americans, are strongly associated with the risk of LN-ESRD as well as
the time to progression to ESRD in African Americans.65 African Americans also
tend to have a less favorable outcome when they undergo renal engraftment,66–69
which relates to a higher number of risk factors for allograft failure (higher rate of
cadaver donors with greater degree of HLA mismatch and higher levels of reactive
antibodies against HLA compared with Hispanics and whites).68 Moreover, lower in-
come levels have been associated with higher risk for graft loss and death among
transplanted African Americans.69
Integument damage occurs more commonly among African Americans,15,18 ocular
damage among Texan Hispanics, and malignancy among whites.15 Diabetes and
alopecia were significantly more frequently among the CLU African Americans49; dam-
age in the musculoskeletal system, particularly avascular necrosis, was commonly
found in African Americans from the Hopkins cohort but not in other published
studies.53
Studies performed in different Asian subgroups (Chinese, Koreans, and Arabs) in

their country of origin have shown that these patients accrue damage at similar rates
to whites, but they tend to accrue more renal but less cardiovascular and ocular dam-
age. In addition, there is variability in the patterns of damage across different Asian
countries, with Chinese patients having a high prevalence of premature gonadal fail-
ure, whereas patients residing in southern and western Asian countries develop
more integument damage, which probably relates to an increased exposure to ultra-
violet B rays.70
As for the Asians residing in western countries, overall damage has been generally
reported to be higher than that observed among the respective white populations, but
this has not been observed in Canada.21,29,30,33,61,70 Asian patients in Canada had the
lowest damage score, and at an average of 10 years of disease, 59% had not accrued
any damage compared with 35% of Afro-Caribbean and 42% of white patients. How-
ever, Asians in Canada had a similar SES to that of whites, and it is possible that this
may have protected them.21
WORK DISABILITY
Illness-related work disability has profound repercussions at the individual and societal
levels, because work loss leads to a diminished self-esteem, income loss, inability to
accumulate assets for retirement, and social isolation. Three to 15 years from diag-
nosis, 15% to 51% of patients with SLE report ceasing employment.71 This outcome
has been associated with several different demographic, disease-related, and job-
related factors, such as older age, lower levels of education, African American
ethnicity, poverty, longer disease duration, higher disease activity and damage scores,
fatigue, fibromyalgia, anxiety, neurocognitive involvement, thrombotic manifestations,
and higher physical job demands.71–77 Thrombotic events have been associated with
an increased risk of acute work loss, whereas musculoskeletal manifestations and
neuropsychiatric events have been associated with delayed work loss.77
When the risk factors for self-reported work disability in patients from the LUMINA
cohort were examined,74 African American and Hispanic (from Texas) ethnicities were
associated with the occurrence of work disability over the course of the disease in uni-
variable analysis; however, poverty along with older age, male gender, disease activ-
ity, damage accrual, and disease duration, but not ethnicity, were retained in the
multivariable models, supporting the importance of socioeconomic factors on the
development of this intermediate outcome and the association between minority sta-
tus and poor SES in the United States and probably elsewhere. Similar findings were
obtained by Utset and colleagues,78 and like in LUMINA, African American ethnicity
was not retained in the multivariable analyses, except when neurocognitive impair-
ment and damage were removed from the model; then, a trend was found.
Work disability has rarely been studied in Asian patients with lupus. In a cross-
sectional questionnaire study performed in Chinese patients,79 a high cumulative inci-
dence of work disability was found (36% at 5 years of diagnosis); in this particular
study, older age, fatigue, and more active disease were independent predictors of
work disability. In another cross-sectional Chinese study,80 the prevalence of SLE-
related complete work disability after median disease duration of 9 years from onset
was 16%. SES (lower levels of education) and disease factors (longer disease duration
and history of having pleurisy) were independently associated with increased risk of
work disability. Neuropsychiatric involvement and a lower utility score (derived from
the Euroqol 5 dimensions, a standardized measure of health status) were not signifi-
cantly associated with work disability in this study.
MORTALITY
Nonwhite patients with SLE have higher mortality than white patients.81–84 Data from
US national mortality statistics showed that African Americans with SLE have a 2-fold
to 3-fold higher risk of death than whites. African American and white women experi-
enced an increase in their mortality between 1979 and 1998, but the proportional
increase has been greatest for the African American women, particularly among those
aged 45 to 64 years. In contrast, mortality among white men declined significantly over
this time, whereas for African American men, mortality has remained essentially
unchanged. No national mortality data for Hispanics were available for the years stud-
ied.81,82 Ethnic disparities in mortality have also been documented in several other
studies; for example, death certificate information was linked to hospitalization re-
cords for patients with SLE in South Carolina for the years 1996 to 2003; again, only
African Americans and whites were included. An SLE-specific comorbidity index, pre-
viously developed as a measure of risk of in-hospital mortality, was used. This index
was higher among African Americans, mainly because of lupus-specific comorbidities,
such as LN, and a greater risk of in-hospital and 1-year mortality after discharge
compared with whites; they were also hospitalized and died at younger ages than their
white counterparts and were more likely to die of infection, especially those younger
than 50 years. Paradoxically, mortality risk differences between African Americans
and whites were more pronounced among those patients with less severe illness
(comorbidity index score of zero), whereas among those with more severe disease,
the difference was not significant; these findings suggest that follow-up care for
African Americans with less severe disease is not of the same quality as that of whites,
emphasizing again the importance of SES in mortality.84 Similarly, SLE annual mortal-
ity between 1968 and 1976 was found to be significantly higher for Asians than for
whites in the United States.83 When exploring whether the type of health insurance in-
fluences the ethnicity-mortality relationship, higher mortality risk for African Americans
than for whites was observed in all the insurance categories (Medicare/Medicaid, pri-
vate, and others, including self-pay and uninsured), indicating that insurance status
per se does not explain disparities in mortality.81
In the LUMINA study, the Kaplan-Meier survival curves have repeatedly shown sig-
nificant differences as a function of ethnicity, with Texan Hispanics and African Amer-
icans having lower survival rates than whites and Puerto Rican Hispanics (Fig. 1);
however, these differences disappeared when adjusting for socioeconomic features,
poverty being the strongest predictor of mortality (Table 2).13,85 Similar data have
emanated from the Hopkins Lupus Cohort, in which African American ethnicity was
not retained in the multivariable analyses after adjusting for demographic con-
founders; instead, lower household income was included in the model.86 Ward and
colleagues87 have shown that SES was more important than race/ethnicity in explain-
ing the increased mortality observed in patients with SLE from ethnic minority groups.
Given that damage accrual has been shown to be a predictor of mortality,13 the role
of specific damage domains in this outcome has been assessed; of these, renal dam-
age has been independently associated with a shorter time to death, but only when
poverty was omitted from the multivariable analyses, emphasizing again the impor-
tance of SES as determinant of poor outcomes in lupus.88
The importance of SES in the survival of patients with lupus has also been recog-
nized in the GLADEL cohort10; patients who died had a lower SES, as determined
by the Graffar method,89 lower education level, and less optimal medical coverage.10
Given that poverty is an important predictor of damage accrual,13 poverty and less
favorable psychosocial factors influence the survival of patients with lupus directly but
Fig. 1. Kaplan-Meier survival curves for LUMINA patients as a function of ethnic group.
African Americans and Texas Hispanics have the lowest survival probability (log rank 5
9.687: P 5 .021). (Adapted from Fernández M, Alarcón GS, Calvo-Alén J, et al. A multiethnic,
multicenter cohort of patients with systemic lupus erythematosus (SLE) as a model for the
study of ethnic disparities in SLE. Arthritis Rheum 2007;57:580.)
also via their modulating effects on damage accrual and disease activity. Therefore,
ethnic differences in disease expression and outcomes, including mortality, are influ-
enced to a greater extent by the interaction of socioeconomic and disease-related fea-
tures than by genetic factors.13,90
Table 2
Poverty is the strongest predictor of mortality in LUMINA patients
Predictors of Mortality at 10 y in LUMINA Patients by Multivariable Cox Proportional Hazards

Regression Analysisa
Variable Odds Ratio 95% Confidence Interval P Value
Age 1.024 1.003–1.046 .023
Povertyb 2.109 1.236–3.517 .006
SLAM-R score at baselinec 1.144 1.103–1.186 <.001
SDI score at baseline 1.186 1.016–1.386 .031
a
Adjusted for gender and ethnicity.
b
As defined by US federal government guidelines.
c
SLAM-R: Systemic Lupus Activity Measure-Revised.
Adapted from Fernández M, Alarcón GS, Calvo-Alén J, et al. A multiethnic, multicenter cohort of
patients with systemic lupus erythematosus (SLE) as a model for the study of ethnic disparities in
SLE. Arthritis Rheum 2007;57:580; with permission.
Ethnic minorities in the United States and around the world have a low SES; among
US Hispanics, a further SES feature is their often limited English proficiency. The result
may be a delay in SLE diagnosis, poor compliance, and less effective treatments for
patients with low SES; in turn, under such circumstances, more damage accumulates,
resulting in higher mortality for them than for the ethnic majority.90
INFLUENCE OF ETHNICITY ON RESPONSE TO LUPUS THERAPY
Data from clinical trials, particularly in LN, suggest that race, ethnicity, and geographic
region may influence treatment response.91–94 Thus, these are important variables to
consider when conducting such trials.
MYCOPHENOLATE MOFETIL AND CYCLOPHOSPHAMIDE IN LN THERAPY IN

MULTIETHNIC POPULATIONS
Induction Treatment
Ethnic differences in renal response to induction therapy with monthly high-dose intra-
venous (IV) cyclophosphamide (CYC) or monthly IV methylprednisolone for severe LN
(mostly proliferative LN) have been reported in a study by the NIH (National Institutes
of Health),95 in which African Americans had an increased probability of developing
renal insufficiency. Similarly, renal survival at 5 years was significantly worse in African
Americans (58%) than in whites (95%) with diffuse proliferative LN from the Glomerular
Disease Collaborative Network after induction with monthly IV CYC following the NIH
protocol.96 Ethnic differences in response to treatment were also observed in patients
with severe LN treated with prednisone and oral CYC (standard therapy) or with stan-
dard therapy plus plasmapheresis. Although the finding was not statistically signifi-
cant, a higher percentage of white patients achieved remission compared with
African American patients (52% vs 29%, P 5 .07); furthermore, African Americans
had a more aggressive renal disease with significantly poorer renal survival and
patient survival at 10 years (38% and 59%, respectively) compared with whites
(68% and 81%, respectively).62
Clinical trials conducted in different countries comparing mycophenolate mofetil
(MMF) and CYC as induction treatment of active LN showed different response rates.
Clinical response (complete or partial remission) rates were high in the study by Chan
and colleagues,97,98 in which Chinese patients were treated with either MMF (95%) or
CYC (90%). In contrast, Ginzler and colleagues,99 using an intention-to-treat
approach, reported a clinical response of 52% in the patients treated with MMF versus
30% for those treated with CYC. More than 75% of patients in this multicenter US
study were of African or Hispanic origin, 17% were whites, and only 6% were Asians.
Differences in design, duration of follow-up, LN category (class IV [Chan and col-
leagues], classes III–V [Ginzler and colleagues]), and patient population can explain
the divergent results of these studies.
The influence of race and ethnicity on response to therapy with IV CYC and MMF
was also observed in the ALMS (Aspreva Lupus Management Study) induction trial
of patients with classes III to V LN.92,93 Important interactions between treatment
group and race (P 5 .047) and geographic region (P 5 .069) were observed. Response
rates with MMF and CYC were comparable in Asian and white patients, but patients in
the combined other and black group (about half African descendants and the rest a
mismatch of patients of different ethnicities) differed significantly in favor of MMF.
This finding was also observed when only the data for the black subgroup was exam-
ined, although in this case, statistical significance was not achieved (Fig. 2). When the
effects of ethnicity were assessed, Hispanic patients were also statistically
Fig. 2. Percentage of patients in the induction study of ALMS responding to treatment, by

race and treatment group; African American is a subset of the other racial group. CI, confi-
dence interval; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil; OR, odds
ratio. (Adapted from Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on
response to lupus nephritis treatment: the ALMS study. Rheumatology 2010;49:133; with
permission.)
significantly more likely to respond to MMF than CYC. Consistent with these findings,
in the intent-to-treat populations analysis, Latin American patients were more likely to
respond to MMF than CYC, but the response rates across the remaining regions (Asia,
United States/Canada, and rest of the world) were comparable (Fig. 3). These results
suggest that the efficacy of CYC varies between racial and ethnic groups and is less
effective in patients of African or Hispanic descent, whereas MMF seems to be consis-
tently effective in all racial/ethnic groups (primarily African Americans and Hispanics).
Probably, the wide variation in response by race/ethnicity for CYC may have been
confounded by regional variations explained by differences in clinical practice.
Furthermore, whether the difference in efficacy in blacks and Latin Americans is real
or caused by shorter treatment duration and fewer doses of CYC among patients in
the black group compared with patients in the other ethnic groups is unclear. More
patients in the black group were likely to withdraw prematurely from the study
because of adverse effects, which led to differences in exposure across ethnic
groups. Differences between subgroups with respect to disease characteristics at
baseline, differences in treatment tolerability, regional patient management, and so-
cioeconomic factors, and ethnic differences in drug metabolism may explain the influ-
ence of race, ethnicity, and geographic region on response to LN induction therapy.93
In a medical records review study of a US multiethnic cohort of patients with prolif-
erative LN (class III–V) treated with either IV CYC or MMF, Rivera and colleagues also
found ethnicity to affect response to therapy. However, unlike the results observed by
Ginzler and colleagues, the response to MMF was superior to CYC after adjusting for
Fig. 3. Percentage of patients in the induction study of ALMS responding to treatment by

region and treatment group. CI, confidence interval; IVC, intravenous cyclophosphamide;
MMF, mycophenolate mofetil; OR, odds ratio. (Adapted from Isenberg D, Appel GB,
Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment:
the ALMS study. Rheumatology 2010;49:133; with permission.)
race, serum creatinine, serum albumin, type of insurance, and LN class; overall,
Asians experienced an excellent response and Hispanics a poor response, which is
also different from the results of the ALMS induction trial. The discrepancy between
the data from these studies may be attributed to the prescribing trends by physicians
in the study by Rivera and colleagues.91 There was greater MMF use in private prac-
tices, whereas those patients unable to afford MMF therapy, or presenting poor prog-
nostic characteristics (abnormal creatinine level, scarring, or fibrosis), were treated
with IV CYC. These data should be interpreted cautiously.
Maintenance Treatment
Maintenance therapy for LN with MMF or azathioprine (AZA) was compared in the
ALMS maintenance trial, showing significant superiority of MMF in patients with active
LN (classes III–V) who had responded to induction therapy with either MMF or CYC.
After 36 months of follow-up, MMF was significantly superior to AZA with respect to
time to treatment failure (the primary end point), time to renal flare, and time to rescue
therapy. The MMF superiority was consistent, regardless of induction therapy
received, ethnicity (whites, African descendants, Asians, and other), and geographic
region. When hazard ratios were estimated in subgroups according to race, the differ-
ential effect between MMF and AZA was more stringent in patients of African
descent.100
Contrary to the results of the ALMS study, in the MAINTAIN (Mycophenolate Mofetil
versus Azathioprine for Maintenance Therapy of Lupus Nephritis) trial,101 MMF was
not found to be superior to AZA as maintenance treatment in patients with proliferative
LN who received a short course of low-dose IV CYC, regardless of whether or not they
had achieved renal response to induction, a significant difference from the
maintenance phase of the ALMS protocol. After 5 years, the primary end point of time
to renal flare did not differ between the 2 groups, with renal flares observed in 19% of
patients treated with MMF and 25% of those treated with AZA. Differences in the
design, in the primary outcome measure, in the number of patients included, and their
ethnicity (different ethnic groups in the ALMS trial, a predominantly white population in
the MAINTAIN study) may explain the divergent results of these 2 studies.100,101
In a study by Contreras and colleagues,102 which included almost entirely patients
of Hispanic and African descent (95%), short-term therapy with IV CYC followed by
maintenance with MMF or AZA was more efficacious, with a lower relapse rate than
long-term therapy with IV CYC. Maintenance therapy with MMF was associated
with a significantly lower relapse rate compared with maintenance with IV CYC pulses,
but there was no difference between MMF and AZA treatment. During the mainte-
nance phase, the doses of CYC were lower than the doses used in the NIH trials, in
which the patients were predominantly white (70%).103,104
CELL-TARGETED BIOLOGICAL THERAPIES: B-CELL–TARGETED THERAPIES AND

COSTIMULATION BLOCKER THERAPY
B-Cell–Targeted Therapies and Ethnicity
B-cell-depleting agents in SLE clinical practice, in particular rituximab, are used in pa-
tients who are intolerant or do not respond to standard therapy, and those with refrac-
tory and life-threatening disease. For the optimal use of this biological agent, some
individual characteristics of the patients, such as ethnicity, organ involvement, and
immunologic profile, should be taken into account.105
Two randomized controlled trials have been conducted to evaluate the efficacy and
safety of rituximab versus placebo. In the EXPLORER (Exploratory Phase II/III SLE
Evaluation of Rituximab) study, patients with SLE with moderate to severe active nonre-
nal SLE were studied, whereas in the LUNAR (Lupus Nephritis Assessment With
Rituximab) study, patients with ISN/RPS class III or IV LN were studied; these trials
did not achieve their primary end points, clinical and renal response, respectively.106,107
However, in the EXPLORER study,106 a prespecified subgroup analysis detected the
highest percentage clinical response to rituximab (major and partial response: 33.8%)
and the lowest clinical response to placebo (major and partial response: 15.7%) among
African American and Hispanic patients, which may have been related to a more active
and refractory disease in these patients. In the LUNAR study,107 a higher proportion of
patients of African descent (vs patients of other races/ethnicities) achieved a renal
response with rituximab compared with placebo, although this was not statistically
significant. Nevertheless, data accumulated at different centers across the world sug-
gest that rituximab is efficacious in patients with SLE with refractory disease.105,108
In the BLISS-52 (Study of Belimumab in Subjects With Systemic Lupus Erythema-
tosus) trial, a better response to belimumab (BLyS-specific inhibitor) was observed
in patients from Eastern Europe compared with patients from Asia and Latin America;
however, the difference between the regions was not statistically significant. Patients
with severe LN and active central nervous system involvement where not included in
this trial, which limits the generalizability of these results to these subgroups of
patients.109
Costimulation Blocker Therapy (Abatacept)

The ACCESS (Abatacept and Cyclophosphamide Combination Efficacy and Safety
Study) trial for LN110 examined the value of adding abatacept (a fusion protein of
IgG-Fc plus CTLA4, which binds to CD80 to block the costimulatory signal to T cells)
to the Euro-Lupus Nephritis Regimen111 in an ethnically diverse population of North

American patients with SLE (39% African American and 40% Hispanic/mestizo) with
class III or IV LN. The primary end point was not achieved; however, the study showed
the benefit of adding abatacept to the Euro-Lupus Nephritis Regimen, which had been
previously evaluated in a predominantly white population; this regimen showed a com-
plete response rate of greater than 30% within 24 weeks in this ethnically diverse pop-
ulation, which is higher than that reported in previous LN trials (including studies of
MMF and IV CYC), suggesting that the Euro-Lupus Nephritis Regimen may have wider
applicability. Furthermore African American patients receiving abatacept had a better,
albeit not significant, response rate than those receiving saline (33% vs 16%).110
ETHNIC DISPARITIES IN RENAL REPLACEMENT THERAPIES IN LN
Ethnic disparities in renal replacement therapies have also been reported among pa-
tients with ESRD secondary to LN.112,113 Devlin and colleagues using the US Renal
Data System from 1995 to 2006, found sociodemographic differences in the initial
choice of renal replacement therapies (peritoneal dialysis [PD], hemodialysis [HD],
or preemptive kidney transplantation) for incident LN ESRD. Race, ethnicity, employ-
ment, and medical insurance type were strongly associated with initial kidney replace-
ment therapy choice. HD was the predominant initial dialysis modality (85%), followed
by PD (12.2%), whereas 2.8% of patients proceeded directly to kidney transplanta-
tion. HD was the prevailing modality in African Americans. Compared with patients
receiving HD, those who received initial PD were more frequently women, of white
or Asian ethnicity, employed, privately insured, in better general health (higher levels
of hemoglobin and albumin), albeit they were more likely to be hypertensive, whereas
cardiovascular comorbidities and the inability to ambulate were associated with low
use of PD. Geographic differences, with a lower proportion of the initial PD than HD
in patients living in the southern United States and a higher proportion in the western
United States were observed. Compared with patients receiving dialysis, those who
underwent preemptive renal transplantation were significantly younger, of white and
non-Hispanic ethnicity, privately insured, employed, and less often from the southern
United States.113 In those patients with SLE who underwent renal transplantation,
African Americans have an increased risk of recurrent LN67 and allograft loss.66,69 In
African American patients, low income levels are significantly associated with higher
risk for engraftment loss and death. In comparison, among non–African American
LN recipients, income levels are not predictive of transplant outcomes.69
Ethnic disparities in renal replacement therapies may also be attributed to physician
beliefs regarding the benefits of transplantation in certain populations. According to a
survey conducted among US nephrologists, they were less likely to believe that trans-
plantation prolongs survival for African Americans than for whites. Furthermore, they
noted that African Americans are less likely than whites to be evaluated for transplan-
tation because of their own preferences, the availability of living donors, failure to com-
plete evaluations, and comorbidities. On the other hand, African American patients
were less likely than white patients to report receiving information about transplantation
from their nephrologists, suggesting that these physicians may provide less information
to their African American patients or communicate less effectively with them.114
Limited geographic access to PD services may explain the high proportion of US
patients with ESRD started on HD. PD availability is greater in metropolitan cities
and the northeast but more limited in the south, midwest, and rural regions. PD ser-
vices are also less available in hospital referral regions, with a greater representation
of African American, Asian, and Hispanic patients with ESRD.115
Geographic variability in access to transplant organs also affects preemptive renal

transplantation rates. Lower rates of wait-listing for and receipt of kidney transplants
among patients with ESRD in the southern United States have been reported.113,116
Patients with ESRD living in rural areas have an increased morbidity and a poorer sur-
vival, because they have less access to academic centers, have a delay in being
referred to nephrology, start dialysis late, and have lower rates of being wait-listed
for kidney transplantation and of transplantation per se.117,118
SUMMARY
Both the genetic and nongenetic components of ethnicity influence the expression
and outcomes of SLE. Genetic factors seem to play a more important role early in
the disease as determinants of the differences observed between SLE patients
from diverse ethnic groups, whereas nongenetic factors seem to play a more impor-
tant role over the course of the disease. Moreover, ethnicity influences response to
SLE treatment, and therefore, it is important to consider when different therapies
are being evaluated. By and large, SLE is more frequent, with less favorable out-
comes in nonwhite populations. To overcome these differences and reduce the
immediate-term, mediate-term, and long-term impact of SLE among disadvantaged
populations, it is essential to increase disease awareness, to improve access to
health care, and to provide care to these patients in a consistent manner regardless
of the severity of their disease.
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95. Austin HA 3rd, Boumpas DT, Vaughan EM, et al. Predicting renal outcomes in
severe lupus nephritis: contributions of clinical and histologic data. Kidney Int
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96. Dooley MA, Hogan S, Jennette C, et al. Cyclophosphamide therapy for lupus
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98. Chan TM, Tse KC, Tang CS, et al. Long-term study of mycophenolate mofetil as
continuous induction and maintenance treatment for diffuse proliferative lupus
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T h e Im m u n o p a t h o l o g y o f
Cutaneous Lupus
Erythematosus
a a,b,
Mark G. Kirchhof, MD, PhD , Jan P. Dutz, MD *
KEYWORDS
Cutaneous lupus erythematosus Discoid lupus erythematosus Chemokine
Interferon-a Cytokine
KEY POINTS
Cutaneous manifestations of lupus erythematosus occur frequently in systemic lupus
erythematosus (SLE), may occur in the absence of systemic disease, and may precede
the diagnosis of SLE.
Proposed pathophysiologic mechanisms are common to cutaneous lupus erythematosus
(CLE) and SLE, suggesting that response to skin disease may provide proof of principle for
therapy for this disease.
Ultraviolet (UV) light is a prominent trigger factor, and increased interferon (IFN)-a produc-
tion is a common initiator of CLE.
Novel treatment strategies are aimed at maximizing inhibition of IFN-a production and
other potentially pathogenic cytokines.
INTRODUCTION
SLE is an autoimmune disease that is characterized by the development of autoanti-

bodies and immunologic attack of different organ systems, including the skin. This
review aims to provide an overview of some of the pathogenic processes that may
be important in the development of SLE, specifically CLE, and then illustrates how
therapies might be tailored to modify these processes and treat disease.
Clinical Manifestations
The American College of Rheumatology (ACR) criteria for the diagnosis of SLE include
hematologic parameters such as elevated levels of antinuclear antibodies, end organ
Disclosure: JPD is funded by a Senior Scientist award at CFRI.

a
Department of Dermatology and Skin Science, University of British Columbia, 835 West 10th
Avenue, Vancouver, British Columbia V5Z 4E8, Canada; b Child and Family Research Institute,
University of British Columbia, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4,
Canada
* Corresponding author. Department of Dermatology and Skin Science, University of British
Columbia, 835 West 10th Avenue, Vancouver, British Columbia V5Z 4E8, Canada.
E-mail address: Jan.Dutz@vch.ca

456 Kirchhof & Dutz
involvement such as lupus nephritis, and mucocutaneous manifestations.1 In order to

make a diagnosis of SLE, 4 of the 11 1982 ACR criteria need to be met.2 Given these
criteria, it is possible for someone to have a diagnosis of SLE despite the fact that the
person may only have mucocutaneous manifestation of disease. Newer criteria have
attempted to redress this imbalance and include new knowledge on the role of autoan-
tibodies and low levels of complement.3 Cutaneous lesions may present years before
the development of systemic disease.4 Progression to systemic disease may occur
in as many as 18% by 3 years.5 As such any discussion of the cause of CLE must include
pathogenic processes inherent to SLE. Specific skin lesions of lupus (those in which his-
tologic changes are diagnostic of lupus of the skin) can be divided into 3 broad cate-
gories based on the chronologic age of lesion. Acute cutaneous lupus classically
presents as nonscarring erythema over the malar region. Subacute cutaneous lupus
erythematosus (SCLE) can present clinically in a variety of ways, but the 2 most com-
mon are annular/polycyclic plaques and psoriasiform or papulosquamous plaques.
Finally, chronic cutaneous lupus erythematosus (CCLE) is perhaps the largest and
most diverse cutaneous form of lupus with lesions that vary from lupus panniculitis to
classic discoid lupus to chilblain lupus. The presence of CLE can give clues to systemic
manifestations in SLE. For example, CCLE in patients with SLE is associated with leuko-
penia, photosensitivity, and anti-Smith serology but decreased risk of serositis and
renal disease.6 Given a potential overlap in pathogenesis, and the ability to reliably mea-
sure skin disease activity, the skin has become a target organ of interest in the develop-
ment of new pharmaceuticals for the treatment of SLE.7
PATHOGENESIS OVERVIEW
SLE, like many other autoimmune conditions, is the result of a complex interplay
between various pathogenic processes. Primary to the development of lupus is an
underlying genetic predisposition to the disease. In a genetically predisposed individ-
ual, it is thought that some sort of trigger initiates the disease processes. In the case
of lupus, these triggers may include infections, hormones, UV radiation, and exposure
to drugs and chemicals. These triggers initiate an inflammatory process that is
concomitant with exposure to autoantigens, likely through the antigens released by
apoptotic cells. Neutrophils and dendritic cells (DCs) may also play an important
role in the initiation of disease. Numerous cytokines and chemokines are involved in
propagating inflammatory responses, suppressing tolerogenic components of the im-
mune system, recruiting immune cells, and promoting the activation of B and T cells.
Autoreactive B cells are intrinsic to the pathogenesis of lupus because they produce
the autoantibodies that are part of the diagnostic criteria of lupus and key in the clinical
manifestations of the disease. Intrinsic to pathogenesis of lupus are numerous feed-
back loops that amplify the immune response and ultimately lead to damage to end
organs such as the skin.
TRIGGERS
Genetics
Genetics plays an important role in the development of lupus, exemplified by the fact
that lupus has a 25% concordance rate among monozygotic twins compared with a
2% concordance for dizygotic twins.8 There have been numerous lupus-associated
genes identified that individually confer a modest risk of developing lupus.9
These genes mediate the function of immune cells such as B and T cells, antigen-
presenting, cells and neutrophils and cellular signaling processes based on IFN
and other cytokines, as well as toll-like receptors (TLRs) and nuclear factor kB.10
The Immunopathology of CLE 457
Lupus-associated genetic changes are also linked to the clearance of nuclear debris,
apoptotic cells, and immune complexes. One of the most commonly reported
polymorphisms to predispose to the development of lupus is the major histocompat-
ibility complex (MHC) genotype including HLA-DR3, HLA-DR2, and HLA-DRB1. Defi-
ciencies of the complement pathway are also strong risk factors for the development
of lupus or lupus-like conditions. Overall, there have been well over 40 genes identified
as potentially contributing to the development of lupus.10 CLE has been associated
with polymorphisms near the locus of the skin-expressed IFN-k gene,11 and in poly-
morphisms of the TYK2, IRF5, and CTLA4 genes,12 all also associated with SLE sug-
gesting a similarity in pathogenesis.
UV Light
UV light is a well-known trigger of CLE, and photosensitivity was one of the criteria
used to make the diagnosis of SLE in the 1982 ACR classification. The role of UV light
in the genesis of CLE lesions has recently been reviewed13: UV light has numerous
important effects in the pathogenesis of lupus including induction of a proinflamma-
tory environment and apoptosis of keratinocytes.14,15 On UV exposure, the proinflam-
matory cytokines IFN-a, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a are
secreted.14,16,17 UV radiation also upregulates intracellular adhesion molecule expres-
sion and induces the secretion of chemokines that facilitate homing of immune cells to
the skin.18 UV radiation is absorbed by DNA of keratinocytes and results in alterations
such as the formation of strand breaks or cyclobutane pyrimidine dimers.19 The
combination of proinflammatory cytokines and DNA damage results in significant ker-
atinocyte cell death. The apoptotic keratinocytes release potential autoantigens, such
as Ro52, that can serve as a stimulatory nidus for autoreactive B and T cells.20 UV
radiation also induces the expression of nuclear antigens on the surface of keratino-
cytes, and this may be related to the strong association of anti-Ro and anti-La to cuta-
neous forms of lupus.21 UV-oxidized DNA is resistant to degradation by cytosolic
nucleases such as TREX1, potentiating immune sensing by cytosolic receptors that
promote inflammatory IFN-a production.22 Overall, UV radiation promotes an autoim-
mune state that initiates a pathogenic process intrinsic to lupus.
Infections
Numerous infections have been linked to the development or the flare of lupus. Pro-
posed mechanisms for this include molecular mimicry, superantigen stimulation of im-
mune cells, epitope spreading, and alterations to the activation and survival of immune
cells. Among the commonly implicated viruses associated with lupus are cytomega-
lovirus (CMV), hepatitis C, and Epstein-Barr virus (EBV). High levels of EBV antibodies
have been correlated with skin and joint manifestations of lupus.23,24 The prevalence
of EBV antibodies is higher in patients with lupus than in the general population.
Molecular mimicry has been noted with EBV. Autoantibodies from patients with lupus
(notably anti-Ro, noted in photosensitive lupus) are able to bind EBV antigens, and
conversely, anti-EBV antibodies can cross-react with autoantigens commonly associ-
ated with lupus, such as double-stranded (ds) DNA.25 EBV-infected B cells may
become resistant to apoptosis and thereby overcome tolerogenic mechanisms.26
CMV has also been associated with lupus development, determined by correlating
the levels of anti-CMV immunoglobulin (IgM) or CMV DNA and the onset or flare of
lupus. CMV infection has been shown to induce expression of 60-kDa Ro on keratino-
cytes.27 Likewise, bacterial infections may stimulate the immune system as bacterial
PAMPs (pathogen associated molecular patterns) bind TLRs, which stimulate plasma-
cytoid DCs cells to produce IFN and facilitate the production of autoantibodies.
458 Kirchhof & Dutz
Drugs and Chemicals

It has been well established that certain medications can induce both SLE and CLE. This
is exemplified by IFN-a-induced lupus, during the treatment of infections and neo-
plasms.28 Anti-TNF-a medications used in a variety of autoimmune diseases have
been shown to induce lupus-like cutaneous eruptions.29 This fact may relate to local in-
duction of IFN-a in the skin, noted in psoriasiform eruptions induced by anti-TNF ther-
apy.30 Induction of SCLE has been linked to terbinafine, calcium channel blockers, and
hydrochlorothiazide, all drugs that potentiate photosensitivity.31 Up to one-third of all
cases of SCLE may be attributed to such drug exposure.32 The relationship between
cigarette smoking and lupus is controversial. Cigarette smoking has been proposed
to increase the levels of proinflammatory cytokines such as TNF-a,33 thus possibly pre-
disposing to the onset or worsening of lupus. In addition, several studies have shown a
decrease in the effectiveness of antimalarial therapy on CLE in patients who smoke.34
Hormones
The observation that SLE is far more frequent in premenopausal women suggests that
there is a significant hormonal component to the pathogenesis of lupus. Furthermore,
flares of SLE have been associated with changes in hormones such as those seen in
pregnancy or from exogenous administration of hormones either as replacement ther-
apy or contraception. Estrogens and prolactin promote the survival and activation of
autoreactive B cells, thereby promoting the production of autoantibodies.35 Estrogens
are also able to modulate the polarization of T-helper cells to a TH2 phenotype with
increased production of IFN-a, IL-4, and IL-10 as well as stimulating the production
of TNF-a.36 In CLE, estrogen may facilitate the interaction between keratinocytes
expressing autoantigens and autoantibodies like anti-Ro and anti-La.37 The overall
sex ratio for CLE in one study over a 40-year period was female:male 5 1.8:1, which
thus includes a much higher proportion of males than is common for SLE.4
Apoptosis
Apoptosis of keratinocytes is a key process in the pathogenesis of CLE as has been
demonstrated by the detection of apoptotic keratinocytes in the basal layer of
CCLE lesions and in the suprabasal region of SCLE lesions.38 UV-radiation-induced
apoptosis is a significant stimulant for proinflammatory cytokines and autoantigen
availability.14,16 There is also evidence that apoptosis itself is able to generate novel
autoantigens that are then targeted by autoantibodies.21,39 Phosphorylation of pro-
teins and caspase-mediated protein cleavage are 2 methods active during apoptosis
that generate novel autoantigens. These novel autoantigens may be able to break
tolerance. There also seems to be a decreased level of clearance of apoptotic cells
by macrophages, which may provide more time for the stimulation of autoreactive B
cells and the formation of autoantibodies.40
Cytokines
IFNs
The IFN cytokine family plays a key part in the pathogenesis of lupus; however, much
of the data have focused on IFN-a and IFN-g. IFN-a increases MHC expression, anti-
body production, and lymphocyte survival.41 In patients with SLE, IFN-a serum levels
correlate with disease activity and autoantibody levels.42 The main source of IFN-a in
patients with SLE is the plasmacytoid DC.43 Production of IFN-a by plasmacytoid DCs
is stimulated by immune complexes and, because IFN-a also stimulates autoantibody
production, this produces a feedback mechanism that can quickly generate rapid in-
creases in IFN-a.44 IFN-a-induced proteins are upregulated and plasmacytoid DC
numbers are increased in lesions of skin lupus.45 Furthermore, the IFN-a-induced

gene signature is increased in the blood of patients with CLE and correlates with
the activity of the skin disease.46 Within the skin, IFN-a increases expression of che-
mokines and chemokine receptors, thereby facilitating homing of immune cells to the
active lesions of CLE.47 Furthermore, IFN-a stimulates the expression of death-
inducing molecules such as TRAIL and the death receptor TRAIL-R1 on keratinocytes,
perhaps enhancing local keratinocyte cytotoxicity.48 Epithelial-expressed (type III)
IFNs such as IFN-l have also been suggested to have a primary immune-
stimulatory role in CLE.49 These stromal IFNs may be induced through stimulator of
interferon genes (STING) signaling after the recognition of damaged DNA by cytosolic
DNA receptors such as cyclic GMP-AMP synthase.50 Using elegant transgenic mice
crosses, it has been demonstrated that increased stromal IFN production, such as
the one that occurs if the deoxyribonuclease (DNAse) TREX1 is ablated, is sufficient
to ultimately drive B- and T-cell-mediated lupus-type autoimmunity.51
IFN-g is considered to be a typical TH1 cytokine and promotes cytotoxic immune
responses by upregulating antigen processing and presentation. IFN-g is produced
by natural killer cells and activated TH1 cells. IFN-g has been shown to be elevated
in the serum of patients with SLE and correlates with disease activity.52 A recent
transcriptomic analysis of CCLE skin lesions has shown a lesional enrichment of
INF-g-related genes and a paucity of IL-17-associated genes when compared with
psoriasis.53 The pathogenic effects IFN-g are presumed to be similar to that of
IFN-a involving increased autoantibody formation, increased MHC expression,
increased chemokine and chemokine receptor expression, and generally promoting
an inflammatory state.
TNF-a
TNF-a is produced by keratinocytes on exposure to UV radiation or bacterial endo-
toxin; however, the main source of TNF-a in the epidermis is believed to be mast
cells.54 When keratinocytes from patients with CLE are stimulated with IL-18 (another
proinflammatory cytokine implicated in lupus pathogenesis), TNF-a is produced in sig-
nificant quantities compared with keratinocytes from normal controls.55 TNF-a is
expressed in the lesions of SCLE,56 and SCLE is associated with a TNF-a promoter
polymorphism.57 However, the primordial role of this cytokine in skin disease remains
conjectural because TNF inhibitors have not been singularly effective in treating the
condition and may trigger lupus-like eruptions29 as well as SLE.58
B-lymphocyte stimulator (BLyS) or BAFF

B-lymphocyte stimulator (BLyS/BAFF) is a cytokine and a member of the TNF ligand
family.59 BLyS is expressed by a wide variety of cells including monocytes, neutro-
phils, T cells, and DCs. BLyS promotes the survival, proliferation, and differentiation
of B cells and stimulates immunoglobulin secretion. In patients with lupus, BLyS levels
are elevated in serum and correlate with anti-dsDNA antibody levels. BLyS and BLyS
receptor are also overexpressed in lesional cutaneous lupus skin.60 BLyS expression
can be induced by PAMPs such as CpG, lipopolysaccharide, dsDNA, and peptidogly-
cans suggesting that infectious agents may be able to upregulate BLyS expression.61
These PAMPs can also induce expression of BLyS receptor on B cells through TLR-4-
and TLR-9-based signaling. This fact suggests that there might be a positive feedback
mechanism between the innate immune system and B cells.
IL-6
IL-6 is mainly produced by monocytes, fibroblasts, and endothelial cells.62 IL-6 promotes
the development and maturation of B cells into plasma cells, which ultimately leads to
460 Kirchhof & Dutz
increased levels of autoantibodies.63 Monocytes, fibroblasts, endothelial cells, and ker-

atinocytes have been shown to produce IL-6 when exposed to UV-B radiation.14,64 In
patients with lupus, IL-6 level is elevated in serum and correlates with disease activity
and autoantibody levels.64 In a murine model, keratinocyte-induced IL-6 production pro-
moted SLE.65 IL-6 levels are elevated in the sun-exposed skin of patients with SLE.65
IL-10
IL-10 is generally regarded as an antiinflammatory cytokine, although it can have
proinflammatory effects in certain situations. IL-10 is produced by monocytes and
lymphocytes. IL-10 inhibits T-cell activation and TNF-a secretion, but supports
B-cell proliferation and differentiation as well as immunoglobulin production by B cells
from patients with lupus.66 Immune complexes in the sera of patients with SLE have
been shown to promote IL-10 production.67 A pilot trial of anti-IL-10 antibody therapy
demonstrated improvement in skin and joint disease in 6 patients with SLE.68
IL-17
The IL-17 cytokine is produced by TH17 T cells and has been implicated in numerous
autoimmune conditions including psoriasis and multiple sclerosis. IL-17 is able to
stimulate the production of other proinflammatory cytokines such as IL-6 and TNF-a
and chemokines that attract monocytes and neutrophils to areas of inflammation.69
The receptors for IL-17 are expressed on a variety of cell types and tissues including
T cells, B cells, vascular endothelial cells, and tissues from organs such as the lung,
heart, kidney, and gastrointestinal system. The fraction of TH17 cells in the peripheral
blood of patients with lupus is elevated, and increases in TH17 cells are correlated with
flares of disease particularly with accompanying vasculitis.70 IL-17 levels are elevated
in the serum of patients with lupus and correlate with disease activity and autoanti-
body production. Although elevated levels of IL-17A and IL-17F have been reported
in the serum and skin of patients with SLE and CLE (both CCLE and SCLE),71 a recent
transcriptome analysis of lesional CLE skin did not show an increase in IL-17-related
transcripts in CCLE lesional skin.53
Chemokines
Chemokines are important in recruiting immune cells to areas of inflammation. The
CXCL9, CXCL10, and CXCL11 chemokines are strongly expressed in the lesions of
cutaneous lupus.72 These CXCL chemokines are induced by IFN-a73 and are impor-
tant in the recruitment of CXCR3-positive lymphocytes to the epidermis.74 This fact
is confirmed by the finding of high numbers of CXCR3-positive lymphocytes in lesional
skin with concomitant decreases in circulating CXCR3-positive lymphocytes.74
CXCL10 is most prominent at the interface between the epidermis and dermis where
CXCR3-positive lymphocytes invade the epidermis.75
ADAPTIVE IMMUNE SYSTEM

T Cells
One of the main themes of lupus pathogenesis is the downregulation of tolerogenic
mechanisms that normally control the survival and development of autoreactive
lymphocytes. In particular, the downregulation of T-regulatory cells seems to play
an important role in the development of lupus. Analysis of skin lesions from patients
with CLE shows that levels of Treg cells are reduced in number compared with
those in other inflammatory diseases.76 Transcriptome analysis of lesional skin from
11 patients with CCLE compared with that of psoriasis and normal skin has shown
a skew toward TH1-type T cells and IFN-g production.53
B Cells
The central role of B cells in the development of lupus involves breaking tolerance
resulting in autoreactive B cells and plasma cells that produce autoantibodies. Primary
to this process is the breaks in tolerance that occur both centrally and peripherally.
Deficiencies in early negative selection result in the persistence of mature naive B cells
that have the ability to recognize self-antigens.77 Regulatory B cells in patients with
lupus, although present at similar frequencies to normal control patients, lack the
functionality found in normal control patients.78 B cells are focally increased in lesions
of CCLE,79 but their role in local pathogenesis is unknown.
Autoantibodies
Numerous autoantibodies have been associated with lupus including antinuclear
antibody, anti-dsDNA, anti-SSA/Ro, anti-SSB/La, and anti-Smith.80 The role of these
autoantibodies in the pathogenesis of CLE is unclear. Clinical manifestations of dis-
ease seem to correlate with certain autoantibodies. Anti-SSA/Ro and antinucleosome
antibodies are associated with CLE.81 However, deposition of these autoantibodies
does not necessarily correlate with active disease and autoantibody deposits are
found within clinically normal skin as well as within active lesions.
Complement
The complement system involves both the innate and adaptive immune systems. One
of the most robust associations with the development of lupus is complement defi-
ciency. C1q, C1r, and C1s deficiencies are associated with a high risk of developing
lupus, and specifically CLE.82 Deficiencies in these complement components and
others reduce the ability to clear immune complexes leading to increased availability
of autoantigens. Complement is also important in clearing apoptotic cellular material.
C1q-deficient mice show delayed clearance of apoptotic cells, which leads to second-
ary necrosis.83 C1q is also able to regulate the production of IFN by plasmacytoid
DCs.84 C1q inhibits IFN secretion when plasmacytoid DCs are stimulated by CpG
DNA or immune complexes; therefore, any deficiency in C1q results in increased
IFN secretion.
INNATE IMMUNE SYSTEM

DCs
DCs play numerous roles in the pathogenesis of lupus. DCs phagocytose apoptotic
cells and cellular debris, activate B cells, and secrete proinflammatory and stimulatory
cytokines. Phagocytosis by DCs is important in preventing exposure to self-antigens
and developing immune reactions to the autoantigens.85 DCs from patients with lupus
have been shown to have decreased abilities to phagocytose apoptotic cells.85 DCs
also participate in the stimulation of autoreactive B cells by presenting autoantigens
and releasing stimulatory cytokines such as IFN, IL-6, and BLyS. The importance
of DCs in the development of lupus was demonstrated in lupus-prone mice that devel-
oped less severe systemic disease when their DCs were depleted.86 Inflammatory-
type DCs87 and activated conventional DCs88 are increased within the skin lesions
of lupus.
Neutrophils
Activated neutrophils die in a unique way termed NETosis that differs from necrosis
and apoptosis.89 During NETosis, the neutrophils release large amounts of DNA
that form net- or weblike structures termed neutrophil extracellular traps (NETs). In
462 Kirchhof & Dutz
lupus, NETs are formed when neutrophils are activated by immune complexes con-
taining nucleic acids. Patients with lupus also seem to have neutrophils that are more
likely to release NETs. The DNA within the NETs is protected from degradation. Sera
from patients with lupus have been shown to have an impaired ability to degrade
NETs, and this deficiency is associated with increased levels of anti-dsDNA anti-
bodies.90 This deficient NET degradation may be related to DNase inhibitory anti-
bodies because DNase function is lower in the sera of patients with lupus and NET
degradation can be rescued by exogenous DNase. The DNA associated with the
NETs may act as ligands for TLRs, thereby mediating plasmacytoid DC activation
and IFN production.91 Furthermore, IFN can potentiate NETosis leading to a self-
perpetuating feedback loop. Mouse experiments have suggested the importance of
neutrophils in the development of lupus and CLE: when inflammatory lupus-like
skin disease is initiated by tape stripping, NETosis is noted with increased levels of
IFN production from activated plasmacytoid DCs.92 Increased NETs are detected
in lesional CLE skin.93
TLRs
TLRs, on DCs and B cells, play important roles in the interplay between the innate
immune system and the adaptive immune response. B-cell upregulation of BLyS in
the presence of microbial products depends on TLR-4 and TLR-9 signaling. Reports
have suggested that TLRs may bind and signal not only from engagement of exogenous
ligands but also from endogenous ligands such as UV-damaged DNA.94 TLR-9 or TLR-
7/8 may mediate responses to autoantigens in plasmacytoid DCs, resulting in IFN
production. Treatment of mice with dual TLR-7 and TLR-9 inhibitor causes a decrease
in autoantibody levels and clinical improvement of disease symptoms.95 Overall, TLRs
represent an interesting and growing area of study in the pathogenesis of lupus.
THERAPEUTIC IMPLICATIONS
Photoprotection
Because CLE can be triggered by sunlight exposure, the use of consistent UV light
protection is important. Studies of broad-spectrum sunscreen use before photoprovo-
cation have demonstrated the prevention of UV-induced lesions.96
Topical Therapy
Topical therapy is practical for limited disease. Potent corticosteroids are the first-line
option and are most frequently used.97 Corticosteroids have multiple antiinflammatory
actions on both innate and adaptive immune cells. Recent work suggests that cortico-
steroids may also promote apoptotic cell clearance.98 Topical calcineurin inhibitors
are also effective in improving cutaneous lesions.99 However, once daily use of
clobetasol 0.05% ointment was found to be superior to twice daily use of tacrolimus
0.1%.100
Antimalarial Therapy
The antimalarials, hydroxychloroquine and chloroquine, are first-line therapies for wide-
spread cutaneous disease.101 Hydroxychloroquine response requires adequate blood
levels,102 and thus blood level monitoring may improve outcomes. Response may be
slow, with improvement beyond 2 months, and may be enhanced by the addition of
quinacrine.103 Although it has been proposed that antimalarials improve CLE by inhibit-
ing TLR-7/8 and TLR-9 signaling through an effect on endosomal pH,101 recent work has
suggested that these drugs actively bind nucleic acids and thereby prevent TLR-ligand
interaction104 leading to inhibition of downstream events such as decreased IFN-a
production and IL-6 release. Thus, antimalarial therapy in patients with SLE impairs the
ability of their plasmacytoid DCs to produce INF-a and TNF-a on stimulation with TLR 9
and TLR 7 agonists.105 This mechanism may also explain how chloroquine inhibits IL-1b,
IL-6, and TNF-a release in the skin after UV irradiation in patients with SLE.106
Immunosupressive and Immunomodulatory Therapy

For patients refractory to antimalarials, dapsone, azathioprine, methotrexate, myco-
phenolate mofetil, cyclosporine, retinoids, and thalidomide are therapeutic options.107
The clinical evidence for the use of these agents has been expertly reviewed.107
Roughly 10% of patients are refractory to treatment with these agents,108 and new
options for recalcitrant disease are required.
Methotrexate is an antimetabolite that has multiple modes of action. Analysis of
patients with psoriasis treated with methotrexate has indicated that this drug does
not change the TH1 or TH2 profile of T cells.109 Work from 2 groups has suggested
that one mode of action of this drug may be to alter lymphocyte trafficking, with a
decrease in the proportion of skin-homing cutaneous lymphocyte antigen-bearing
T cells.109,110 Newer agents that may alter skin-homing T-cell traffic, analogous to
agents limiting traffic of T cells to the gut, are eagerly awaited.
Thalidomide has been shown to improve CLE is a prospective study.111 This drug
has been described as one of the most effective for the treatment of resistant CLE,
limited in use by common neurotoxicity.107 Likewise, lenalidomide, a thalidomide
analog, may be of benefit in refractory cases.112 The mechanism of action of thalido-
mide and thalidomide analogs in CLE is still unclear. Apremilast, another thalidomide
analog and phosphodiesterase 4 inhibitor, improved cutaneous skin scores in patients
with chronic CLE.113 This drug inhibits T-cell production of IFN-g,114 among other
cytokines.
Retinoids have been shown to have an efficacy comparable to antimalarials in
the treatment of CLE, their use being limited by common cutaneous side effects
such as skin dryness. In a double-blind randomized trial comparing acitretin with
hydroxychloroquine, improvement occurred in 13 of 28 patients treated with acitretin
and in 15 of 30 patients treated with hydroxychloroquine.115 Isotretinoin (80 mg/d)
has been reported to induce rapid improvement in 8 patients (7 with CCLE and 1
with SCLE) treated, associated with normalization of histology.116 Alitretinoin has
recently been reported to improve single cases of CCLE, SCLE, and hypertrophic
CCLE.117 The mechanism of action of retinoids in CLE is unclear, although isotretinoin
has a prominent effect on T-cell production of IFN-g in acne vulgaris118 and acitretin
also inhibits IFN-g production in psoriasis.119 Because the mode of action differs from
those of antimalarials, combination therapy (retinoid and antimalarial/antimalarials)
may be beneficial in antimalarial-resistant skin disease.120
Few studies to date of T-cell inhibitors or cytokine inhibitors have shown convincing
activity for CLE. Perhaps, given the paucity of lesional IL-17-related transcripts in CLE,
only 3 case reports support an effect of ustekinumab on CLE.107,121,122 The presence
of IFN-g-related transcripts in lesional skin supports trial of inhibitors of this pathway.
Pathway network analysis of genes overexpressed in T cells in SLE suggests that
inhibitors of the JAK/STAT pathways may be therapeutically useful in SLE.123 JAK1
and JAK2 inhibitors block IFN-g production, and topical inhibitors are under develop-
ment.124 JAK1 and JAK3 inhibitors such as tofacitinib, used in rheumatoid arthritis,
may have activity for CLE.125 However, a topical JAK/Syk inhibitor (R333) recently
did not achieve the primary end point in a phase 2 study (http://ir.rigel.com/phoenix.
zhtml?c5120936&p5irol-newsArticle&ID51867780&highlight). A specific monoclonal
antibody blocking IFN-g has been studied in a preliminary manner in CCLE (AMG 811,
464 Kirchhof & Dutz
ClinicalTrials.gov # NCT01164917) and SLE. Although the studies were not powered
to assess efficacy, AMG 811 led to a dose-dependent modulation of the expression
of many of the genes associated with IFN-g signaling and a reduction in CXCL10.126
B-cell-directed therapies have so far demonstrated only a moderate effect on CLE.
B-cell depletion therapy with rituximab in 17 patients with cutaneous manifestations of
SLE resulted in temporary improvement in 53% of patients.127 Belimumab, an inhibitor
of BLyS, and the first drug approved specifically for the treatment of SLE, is noted to
improve rash, mucosal ulcers, and alopecia.128 More rigorous studies of these agents
in CLE with the use of standardized outcome measures such as the cutaneous lupus
activity score index (CLASI)129 are awaited.
Because elevated levels of IL-6 are noted in lupus, and in lesional CLE skin, inhib-
itors for this pathway are currently being assessed as therapeutic agents. One report
details the use of tocilizumab, an antibody to the IL-6 receptor, to treat refractory CLE
and urticarial vasculitis.130 Preliminary data from a phase 1 study of sirukumab (CNTO
136), an antibody to IL-6, demonstrated a decrease in levels of C-reactive protein in
treated individuals and a trend to lower CLASI inflammation scores.131 Further studies
on the effects of this agent on CLE are awaited.
Perhaps the most direct approach to therapy, given the prominence of IFN-a
transcripts within the skin, is direct inhibition of the type 1 IFN pathway. In this regard,
trials of sifalimumab, a monoclonal antibody to IFN-a, have shown inhibition of an IFN-
a-related transcriptome in the skin132 but only modest clinical change in systemic dis-
ease.133 Intravenous immunoglobulin (IVIG) infusions have been used as treatment of
multiple autoimmune diseases. IVIG has been used for severe hematologic and neuro-
logic disease in SLE.134 IVIG use in a mouse model of SLE demonstrated improvement
in skin disease but not renal disease.135 In one study, 5 of 12 patients treated with IVIG
for CLE had excellent response.136 Responders predominantly had SCLE and had
failed multiple other therapies; no changes in immune parameters or systemic disease
were noted. A single case report details the use of IVIG for the successful treatment of
lupus panniculitis, after failure of standard therapy.137 The authors have had a similar
experience with an additional case. IgG has been reported to inhibit IFN-a production
by plasmacytoid DC through both intracellular pathways (promoting prostaglandin E
production) and by Fc receptor blockade.138 IVIG has also been shown to attenuate
TLR-9 response in B cells of patients with SLE who have been treated.139 A preliminary
study to assess the benefit of IVIG in CLE is underway (NCT01841619).
SUMMARY
Because SLE and CLE are clinically heterogeneous diseases, a simple pathophysio-
logical understanding of these diseases remains elusive. There are multiple genetic
similarities between patients with skin-limited and systemic disease, arguing for a
common pathogenesis. The ability to photoprovoke skin lesions argues for an impor-
tant initiator role for UV light. Multiple lines of evidence point to an important role for
abnormal responses to dead and dying cells with either a propensity for cell death
or deficiencies in the noninflammatory clearance of dead cells. Innate immune re-
sponses resulting in the local overproduction of INF-a lead to activation of the adap-
tive immune system at the interface of the dermis and epidermis, thus causing tissue
damage (Fig. 1A). This understanding of the pathways of damage in CLE has clarified
the understanding of the mode of action of commonly used treatments in CLE
such as antimalarial agents and corticosteroids (see Fig. 1B). The primacy of type 1
and possibly type 3 IFN pathways and IFN-g has suggested new therapeutic routes
such as inhibition of IFN-a and blockade of cytokine signaling (see Fig. 1C). It is hoped
A 465
Fig. 1. (A) Model of the pathogenesis of cutaneous lupus erythematosus: Keratinocytes (KC)
are damaged by ultraviolet light or other stimuli and are induced to undergo apoptosis. Either
increased cell death or defective clearance results in an immunostimulatory environment with
stimulation of TLR and cytosolic danger receptors. Neutrophils (Neut) and plasmacytoid den-
dritic cells (pDC) conspire to release INF-a summoning activated inflammatory dendritic cells.
This culminates in TH1 T-cell instruction and B-cell-mediated autoantibody production leading
to further stromal cell damage. (B) Based on the pathogenesis model in (A), currently available
therapies for cutaneous lupus erythematosus are indicated in red at the most likely sites of ac-
tion. (C) Based on the pathogenesis model in (A), investigational therapies and novel thera-
peutic action points are indicated in magenta. STING, stimulator of interferon genes.
466 Kirchhof & Dutz
Fig. 1. (continued)
that these new therapeutic avenues will lead to novel and effective therapies for this
difficult-to-treat disease and suggest strategies for the prevention of disease in the
genetically susceptible.
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P a t h o g e n e s i s an d
Tre a t m e n t o f
Athero sclerosis in Lupus
Maureen McMahon, MD, MS*, Brian Skaggs, PhD
KEYWORDS
Cardiovascular diseases Atherosclerosis Systemic lupus erythematosus
Cytokine Proinflammatory lipids
KEY POINTS
Cardiovascular disease (CVD) is a significant contributor to morbidity and mortality in sys-
temic lupus erythematosus (SLE).
SLE-specific risk factors for accelerated atherosclerosis (ATH) exist but are not well
understood.
Identification of SLE-specific biomarkers and screening tests should provide the means to
recognize at-risk patients.
Current treatment strategies aim to target modifiable cardiac risk factors.
Premature ATH is a major cause of increased morbidity and mortality in SLE. Urowitz
and colleagues1 first described a bimodal pattern of mortality in SLE in 1976, with early
deaths (<1 year) due to SLE disease activity and later deaths primarily due to CVD.
This bimodal pattern has been confirmed in multiple subsequent studies.2 Overall,
there seems to be a 2- to 10-fold increased risk of myocardial infarction (MI) in patients
with SLE compared with the general population.3 The risk is even more striking in
young patients with SLE; for example, Manzi and colleagues4 also found that women
with SLE in the 35- to 44-year age group were over 50 times more likely to have a MI
than women of similar age in the Framingham Offspring Study.
Cardiovascular (CV) events may also result in greater morbidity and mortality in
patients with SLE; patients with SLE have higher risk of in-hospital mortality and pro-
longed length of hospitalizations compared with both diabetic patients and non-SLE,
nondiabetic patients.5 Despite improvements in overall lupus mortality, the increased
Disclosure: None.
Division of Rheumatology, David Geffen School of Medicine, University of California, Los
Angeles, 1000 Veteran Avenue, Room 32-59, Los Angeles, CA 90095, USA
E-mail address: mmcmahon@mednet.ucla.edu

476 McMahon & Skaggs
risk of mortality from CVD seems to have remained constant. Data from a large inter-
national cohort suggest that although standardized all-cause mortality rates (SMR) for
SLE decreased from 4.9 in 1970–1979 to 2.0 in 1990–2001, the SMR for CVD in lupus
did not decrease over the same period.6
PATHOGENESIS OF ATH
The mechanisms of increased and accelerated atherosclerotic risk for patients with
SLE remain to be determined. It is likely that multiple mechanisms are operative,
resulting from a complex interplay between traditional cardiac risk factors and SLE-
driven inflammation.
Even in the general population, it has become clear that ATH is not only a conse-
quence of passive accumulation of lipids in the vessel wall but also a result of inflam-
mation.7 As in the pathogenesis of SLE itself, the interplay of multiple inflammatory
mediators, including leukocytes, cytokines, chemokines, adhesion molecules, com-
plement, and antibodies, results in the formation of atherosclerotic plaques.7 Changes
in the vascular endothelium can accelerate the formation of the atherosclerotic
plaque. In response to hemodynamic stresses such as hypertension,8 inflammatory
mediators such as oxidized low-density lipoprotein (OxLDL), or cytokines such as
interleukin-1 (IL-1) and tumor necrosis factor (TNF), the vascular endothelium un-
dergoes a series of inflammatory changes that result in endothelial cell activation
(ECA).7 Activated endothelial cells upregulate leukocyte adhesion molecules such
as vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1,
and E-selectin.8 Chemoattractant cytokines such as monocyte chemoattractant
protein-1 (MCP-1), IL-6, and IL-8 are also expressed,8 thus inducing a cascade of
proinflammatory, proatherogenic changes in the endothelium that results in the migra-
tion of monocytes into the subendothelial space. T cells are also recruited to the sub-
endothelium by similar mechanisms, although at lower numbers.
Next, low-density lipoproteins (LDLs) are transported into artery walls, where they
become trapped and seeded with reactive oxygen species to become OxLDL.9
OxLDLs in turn stimulate ECA and are also phagocytized by infiltrating monocytes/
macrophages, which then become the foam cells around which atherosclerotic le-
sions are built.7,9 Monocytes and T cells infiltrate the margin of the plaque formed
by foam cells. Muscle cells from the media of the artery are stimulated to grow and
ultimately encroach on the vessel lumen.7 MI occurs when one of these plaques rup-
tures, or when platelets aggregate in the narrowed area of the artery.7
High-Density Lipoprotein Prevents Oxidation and Inflammation

There are many mechanisms designed to clear OxLDL from the subendothelial space,
such as macrophage engulfment using scavenger receptors, and enhanced reverse
cholesterol transport mediated by high-density lipoprotein (HDL).10 Both HDL and
its major apolipoprotein constituent, apolipoprotein A-1 (apoA-1), have also been
shown to prevent and reverse LDL oxidation and ECA.10 Thus, HDL function could
be of equal or even greater importance to HDL quantity in preventing ATH. However,
during the acute phase response, such as in the postsurgical period or during influ-
enza infection, HDL can be converted from the usual antiinflammatory state to proin-
flammatory HDL (piHDL).11 Thus, HDL can be described as a chameleonlike
lipoprotein: antiinflammatory in the basal state and proinflammatory during the acute
phase response.10 This acute phase response, however, can also become chronic
and may be a mechanism for HDL dysfunction in SLE.12
Treatment of Atherosclerosis in Lupus 477
IDENTIFICATION OF PATIENTS WITH SLE AT RISK FOR CV EVENTS

Traditional and SLE-Specific Risk Factors for ATH in SLE
Before therapeutic strategies to prevent CV complications in patients with SLE can be
implemented, it is critical to identify at-risk patients. Traditional Framingham cardiac
risk factors are likely to increase risk in patients with lupus in a similar manner to
the general population. Indeed, traditional risk factors such as hypertension,13–15 hy-
percholesterolemia,1,4,15 diabetes mellitus,1,15 old age,4,14,15 tobacco use,16,17 and
postmenopausal status4,14 have all been associated with atherosclerotic disease in
SLE. Petri and colleagues15 found that 53% of patients with SLE from the Hopkins
Lupus Cohort had at least 3 traditional cardiac risk factors. Some traditional risk fac-
tors may also interact with the management of SLE disease activity; for example,
smoking decreases responsiveness to antimalarial therapy.18,19 Some risks such as
diabetes and hyperlipidemia may also be increased as secondary effects of glucocor-
ticoid therapy,20 whereas others may be directly influenced by SLE disease activity.
For instance, high levels of very-low-density lipoprotein and triglycerides and low
levels of HDL have been described as the lupus pattern and are more strikingly noted
in patients with active disease.21
Although traditional cardiac risk factors clearly play a role in the pathogenesis of
ATH in SLE, they do not fully explain the increased risk. For example, after controlling
for gender, blood pressure, diabetes, cholesterol, smoking, and left ventricular hyper-
trophy in a Canadian cohort, Esdaile and colleagues22 found that the relative risk
attributed to SLE for MI and stroke were 10.1 and 7.9, respectively. In a separate
cohort, Chung and colleagues23 found that 99% of patients with SLE were identified
as low risk using the Framingham risk calculator, with a 10-year risk estimate of
less than 1%; however, 19% of patients with SLE in the cohort had coronary calcium
on electron beam computed tomography (EBCT). Similarly, in an SLE cohort from Tor-
onto, the mean Framingham 10-year risk of a cardiac event did not differ between 250
patients with SLE and 250 controls.24 This study did reveal, however, a higher preva-
lence of nontraditional cardiac risk factors in patients with SLE, including premature
menopause, sedentary lifestyle, and increased waist-to-hip ratio.24 Thus, although pa-
tients with SLE are subject to the same traditional risk factors as the general popula-
tion,22,25,26 these factors do not adequately account for the significantly increased
level of CVD.
SLE-Specific Risk Factors

Disease activity, duration, and damage
The association between SLE disease activity and ATH has been variable. One incep-
tion cohort study found no association between disease activity (measured using SLE-
DAI-2K [systemic lupus disease activity index-2000]) and CV events,27 whereas
several other studies found that higher SLEDAI scores did predict MI and/or
stroke.28–30 Similarly, although one study found that higher mean disease activity
scores were significantly associated with subclinical ATH (increased coronary calcium
scores),31 Manzi and colleagues32 found an inverse relationship between SLE activity
and carotid plaque, whereas several other studies found no association between dis-
ease activity and progression of ATH.33–35 Renal disease activity also seems to be a
risk factor for ATH in patients with SLE; in one large study, both pediatric and adult
patients with end-stage renal disease (ESRD) and SLE had significantly higher mortal-
ity because of CVD than age-matched patients with ESRD who did not have SLE.36 A
history of previous nephritis has also been associated with subclinical ATH in
some37–40 but not all studies.41,42 Interestingly, although low complement levels are
considered markers of disease activity in SLE, several groups have found higher C3
levels to be associated with longitudinal progression of carotid plaque43 and intima
media thickness (IMT)44 and cross-sectional presence of coronary calcium.45
The association between ATH and disease duration and damage in SLE has been
more consistent; several cross-sectional cohort studies have reported significant as-
sociations between longer disease duration and carotid plaque32,42 and coronary cal-
cium scores.31,37 Higher Systemic Lupus International Collaborating Clinics damage
index scores have also been associated with coronary artery disease (CAD),46 pro-
gression of coronary calcium,47 and carotid plaque both in a cross-sectional42 and
in a longitudinal study.33
POTENTIAL BIOMARKERS FOR ATH IN SLE
It would be ideal for clinicians to have a biomarker or biomarker panel that could easily
identify patients at future risk for CVD. Multiple potential biomarkers have been iden-
tified, although most of these are still in the preliminary phases of investigation. The
following discussion highlights novel biomarkers with the strongest evidence,
including those that have been associated either with CV events or with prospective
longitudinal measures of subclinical ATH. Many other potential biomarkers have
been identified in cross-sectional studies; Table 1 includes those biomarkers that
have evidence of an association even after accounting for potential confounding fac-
tors by using multivariate analysis.
Antiphospholipid Antibodies
Although antiphospholipid antibodies (aPL) cause venous and arterial clotting and
have been associated with MIs in the general population,48 the association with
ATH in patients with SLE has been inconsistent. In the LUMINA (Lupus in Minorities:
Nature vs Nurture) cohort study, aPL were an independent risk factor for CV or cere-
brovascular events.49 In the Hopkins Lupus cohort, lupus anticoagulant was the only
antiphospholipid associated with MI.50 More recently, however, there was no associ-
ation of aPL with events in an inception cohort of 1249 patients with SLE.27 Several
studies using measures of subclinical ATH have not found any significant associations
with aPL after adjustment for confounding factors.32,41,42,51
C-Reactive Protein
C-reactive protein (CRP) is a well-established predictor of CV events in the general
population, especially in combination with hypercholesterolemia.52 It is thought that
CRP is not solely a marker of systemic inflammation, but rather may play a direct
role in the pathogenesis of ATH. For example, CRP has been shown in vitro to activate
complement53 and stimulate endothelial cells to express adhesion molecules54 and
MCP-1.55 In subjects with SLE, however, the role of CRP as a predictor of ATH is
less clear. Elevated CRP levels have been associated with CV events in the LUMINA
cohort,16,56 and high-sensitivity CRP (hs-CRP) levels were associated with CV mortal-
ity in a prospective Swedish lupus cohort.57 hs-CRP has also been associated with
both cross-sectional58 and longitudinal progression of carotid IMT.34 Several other
studies, however, did not find an association between ATH and CRP in SLE.35,41,42,59
Proinflammatory HDL
As noted above, antiinflammatory HDL function is as important as quantity in the pre-
vention of ATH.10 During states of chronic inflammation, such as in patients with SLE,
HDL can be converted from the usual antiinflammatory state to the proinflammatory
form and can actually increase oxidation of LDL and inflammation.11 The author’s
group has found that HDL function is abnormal in many women with SLE; 45% of
women with SLE, compared with 20% of patients with rheumatoid arthritis and 4%
of controls, had piHDL that was unable to prevent oxidation of LDL.12 HDL dysfunction
has also been described in primary antiphospholipid syndrome, because HDL isolated
from patients with antiphospholipid syndrome had blunted beneficial effects on
VCAM-1 expression, superoxide production, and monocyte adhesion after activation
of human aortic endothelial cells.60 Subsequent studies in the authors’ longitudinal
cohort of 300 patients with SLE and 168 controls have demonstrated that piHDL is
strongly associated both with cross-sectional41 and longitudinal progression of ca-
rotid plaque and IMT.35
Paraoxonase
Serum paraoxonase 1 (PON1) is a serum esterase that is secreted primarily by the liver
and is associated with HDL in plasma. PON1 has been identified as one of the impor-
tant components of HDL that prevents lipid peroxidation and blocks the proinflamma-
tory effects of mildly OxLDL.10 Decreased levels of PON activity have also been
associated with ATH in the general population.61 Altered levels of PON activity have
also been seen in patients with SLE. In one study, PON activity was reduced in pa-
tients with SLE and antiphospholipid syndrome compared with controls, although
there was no reduction in the total antioxidant capacity of the plasma.62 In another
study of 55 patients with SLE, titers of anti-apoA-1 antibodies were inversely corre-
lated to PON1 activity, and in vitro studies confirmed that apoA-1 antibodies have a
direct inhibitory effect on PON activity.63 Decreased PON activity has been associated
with increased carotid artery IMT and abnormal-flow-mediated dilation in patients with
primary antiphospholipid antibody syndrome60 and was also associated with athero-
sclerotic events in a small cross-sectional study of 37 patients with SLE.64
Adipocytokines
The adipokine leptin is an anorectic peptide that acts on the hypothalamus to modu-
late food intake, body weight, and fat stores.65 Obese people have high circulating
leptin levels, but they develop leptin resistance similar to insulin resistance in type II
diabetes.65 Hyperleptinemia in the general population associates with hypertension,
metabolic syndrome, oxidative stress, and ATH.65 Conversely, adiponectin levels
are inversely correlated with adipose tissue mass66 and are reduced in type II diabetes
and CVD.66
Several small cohort studies have shown elevated leptin levels in adult67–69 and pe-
diatric70 patients with SLE. In the authors’ cohort, leptin levels were significantly higher
in patients with SLE with carotid plaque than in those without plaque and also weakly
correlated with carotid IMT in both a cross-sectional71 and a prospective longitudinal
study35 even after accounting for confounding factors such as age, hypertension, and
diabetes. In another cohort, adiponectin levels were significantly and independently
associated with carotid plaque in SLE.72 However, Chung and colleagues73 found
no significant relationship between leptin or adiponectin levels and coronary calcifica-
tion in SLE.
Homocysteine
Homocysteine is another predictor of ATH in the general population.74 Homocysteine
may play a direct role in the pathogenesis of SLE through its toxic effects on the endo-
thelium.75 Homocysteine also increases free oxygen radicals,76 stimulates monocytes
to secrete MCP-1 and IL-8,77 enhances foam cell formation in vessel walls,78 and is
480
McMahon & Skaggs
Table 1
Traditional and nontraditional cardiac risk factors in patients with SLE
Biomarkers Studies Demonstrating Significant Association with Overt Clinical or Subclinical ATH Reference
72
Adiponectin Higher levels associated with carotid plaque in cross-sectional study of 119 patients with SLE
and 71 controls
140
Annexin A5 Increased carotid IMT and abnormal flow-mediated dilation, cross-sectional study of 133
patients with SLE
49,50
Antiphospholipid Associated with cardiovascular events in 2 cohort studies, but not with events in another large ; not associated27,32,41,42,51
antibodies inception cohort of 1249 patients with SLE
141
ADMA Associated with arterial stiffness but not carotid ATH in a cross-sectional study of 125 patients
with SLE
43–45,58
C3, C5a Increased C3 levels associated with carotid plaque progression in 217 patients with SLE and
104 controls; C3 and C5a associated with carotid IMT progression in 101 patients with SLE;
also associated with coronary calcium in cross-sectional study of 75 patients with SLE; also
associated with increased aortic stiffness
CRP/hs-CRP Associated with cardiovascular events and mortality in 2 large SLE cohorts; associated with Positive association 16,34,56–58
cross-sectional and longitudinal IMT progression in some but not all studies No association: 35,41,42,59
142
Erythrocyte NO Negatively associated with carotid IMT in a cross-sectional study of 191 subjects with SLE and
production RA (data combined)
72,143
E-selectin Higher levels associated with carotid plaque in cross-sectional study of 119 patients with SLE
and 71 controls and with cross-sectional coronary calcium in 109 patients with SLE and 78
controls
144
FAB4 Associated with increased carotid IMT, cross-sectional study of 60 patients with SLE and 34
controls
24,33,37,44,47,82–85
Homocysteine Associated with stroke and arterial thrombosis in a prospective cohort study of 337 patients ;
42,45,51
and with subclinical ATH in several (but not all) longitudinal and cross-sectional cohorts not associated:
143
ICAM Associated with cross-sectional coronary calcium in 109 patients with SLE and 78 controls
145,146
Type I IFN activity Decreased endothelial function, increased IMT, increased coronary calcification in cross-
sectional study of 95 patients with SLE, 38 controls
35,71
Leptin Associated with carotid plaque in cross-sectional study of 250 SLE, 122 controls; also associated
with plaque in longitudinal study of 210 SLE, 100 controls

39,84,147
OxLDL; Ox-PAPC OxLDL showed positive association with a history of CVD in 2 small retrospective case-control
studies of subjects with SLE with CVD vs without and in one cross-sectional study of carotid
IMT; Ox-PAPC associated with carotid IMT in cross-sectional study of 178 patients with SLE
84 148,149
Autoantibodies to OxLDL Positive association with a history of CVD in a retrospective case-control study of 26 subjects ; no association
with SLE subjects with CVD and 26 without
150
Antioxidized Low levels associated with higher carotid plaque in cross-sectional study of 144 patients, 122
phosphatidylserine controls
151
Anti-PC antibodies Inversely correlated with the presence of vulnerable carotid plaques in 114 patients with SLE
and 122 controls
35,41
piHDL Associated with cross-sectional carotid plaque and IMT in 276 patients with SLE and with
longitudinal carotid plaque and IMT progression in prospective cohort of 210 patients with
SLE and 100 controls
143
TNF-a Associated with cross-sectional coronary calcium in 109 patients with SLE and 78 controls
35
sTWEAK Associated with longitudinal carotid plaque progression in prospective cohort of 210 patients
Treatment of Atherosclerosis in Lupus

with SLE and 100 controls
143
VCAM Associated with cross-sectional coronary calcium in 109 patients with SLE and 78 controls
100
Low levels of vitamin D Associated with carotid plaque in cross-sectional study of 51 subjects with SLE
152,153
vWf Associated with cardiovascular events in longitudinal prospective cohort of 182 patients with
SLE
142
Whole blood viscosity Positively associated with carotid IMT in cross-sectional study of 191 patients with SLE and
subjects with RA (data combined)
Abbreviations: ADMA, asymmetric dimethylarginine; CRP, C-reactive protein; FAB4, fatty-acid-binding protein 4; hs-CRP, high-sensitivity CRP; ICAM, intercellular
adhesion molecule; IFN, interferon; NO, nitric oxide; Ox-PAPC, oxidized phospholipids on LDL; PC, phosphorylcholine; RA, rheumatoid arthritis; sTWEAK, soluble
TNF-like weak inducer of apoptosis; vWf, von Willebrand factor.
481
prothrombotic.79 Hyperhomocysteinemia can result from increased age, renal insuffi-

ciency, medications such as methotrexate, as well as genetic and/or dietary
factors.80,81
In one cohort study of 337 patients with SLE, hyperhomocysteinemia was an inde-
pendent predictor of stroke and CV events.82 In several other studies, elevated levels
of homocysteine in SLE correlated with cross-sectional24,37,83–85 and longitudinal
progression33,44,47 of subclinical ATH in SLE. In other recent studies of SLE, however,
homocysteine levels did not correlate with ATH.42,45,51
Biomarker Panels
Through the longitudinal cohort study of CVD in SLE at University of California Los
Angeles, the authors have identified several potential biomarkers for the progression
of subclinical ATH. These biomarkers include piHDL, leptin levels greater than or
equal to 34 ng/mL, soluble TNF-like weak inducer of apoptosis levels greater than
373 pg/mL, homocysteine levels greater than or equal to 12 mmol/L, age greater
than or equal to 48 years, and history of diabetes.35 Although each identified variable
was predictive for the longitudinal development of carotid plaque in multivariate anal-
ysis, no individual variable reflected a balanced risk profile with strong positive predic-
tive value (PPV) and negative predictive value (NPV), specificity (Sp), and sensitivity (Sn).
For example, presence of diabetes had 98% Sp for the presence of plaque in the
authors’ cohort; however, Sn was only 13%.35
The authors next hypothesized that a panel of predictors may give a more complete
assessment of atherosclerotic risk than any one individual predictor. Using this theory,
they created a risk variable, PREDICTS (Predictors of Risk for Elevated Flares, Dam-
age Progression and Increased Cardiovascular Disease in SLE), with low risk defined
as the baseline presence of 0 to 2 predictors and high risk as 3 or more predictors or
diabetes plus more than 1 predictor. In multivariate analysis controlling for other CV
risk factors and disease factors, patients with high baseline PREDICTS risk had a
27.7-fold increased odds ratio (OR) for any carotid plaque at baseline or follow-up
(P<.001), a 15.5-fold increased OR for new plaque progression, and 8.0-fold increased
OR for IMT progression (P<.001). The high PREDICTS variable had an NPV for plaque
presence of 94%, a PPV of 64%, Sp of 79%, and Sn of 89%, giving this combination
variable better overall predictive value compared with any individual marker.35 This
panel needs to be refined and validated in other SLE cohorts, but it does highlight
the concept that a combination of risk factors may more accurately capture the pro-
cesses that lead to the development of ATH than any individual marker.
SUBCLINICAL MEASURES OF ATH
CV events are the gold standard outcome measurement in ATH clinical trials and
cohort studies. However, the length of time required for cardiac events to accumulate
combined with a desire to detect and initiate preventive treatments in by the authors
before the onset of CV damage has led to the development of surrogate markers. A
variety of surrogate measurements have been used to detect the incidence of subclin-
ical ATH in patients with SLE. In a cross-sectional study using carotid ultrasonography
as a surrogate measure, Roman and colleagues42 found that carotid plaque was pre-
sent in 37% of patients with SLE compared with 15% of controls. In a short-term lon-
gitudinal follow-up study in this cohort, ATH developed or progressed in patients with
SLE at an average rate of 10% per year. Further studies using carotid plaque as a sur-
rogate measure have reflected similar prevalences32,33,51 and rates of progression43 of
subclinical ATH in SLE. Furthermore, a recent prospective observational study by Kao
and colleagues86 found that both baseline carotid IMT and presence of plaque were
predictive of future CV events independent of traditional CV risk factors and medica-
tion use.
Other modalities have also been used to screen for subclinical ATH in patients with
SLE. In one study using EBCT, coronary calcification was present in 31% of patients
with SLE compared with 9% of controls.51 In another study using dual-isotope sin-
gle-photon emission computed tomographic myocardial perfusion imaging, 38%
of patients with SLE had perfusion defects.87 When another marker of subclinical
ATH, endothelial dysfunction, was evaluated by ultrasonography, 55% of patients
with SLE had impaired flow-mediated dilation compared with 26.3% of control
subjects.88
In addition to abnormalities of the macrovasculature in SLE, there is evidence to
suggest abnormal coronary microvascular function. When positron emission tomogra-
phy was used, abnormal coronary flow reserve was seen even in patients with SLE
with normal coronary arteries.89 Abnormal stress myocardial perfusion imaging
(shown by adenosine stress cardiac magnetic resonance imaging) was found in
44% of patients with SLE with angina and chest pain in the absence of obstructive
CAD; quantitative myocardial perfusion reserve index (MPRI) was also observed to
be lower in patients with SLE than controls, and the presence of SLE was a significant
predictor of MPRI.90 It should be reiterated, however, that although these measures of
subclinical ATH are significantly linked to coronary events in the general population,91
only abnormal carotid IMT, plaque, and myocardial perfusion have been shown to pre-
dict future CV events in SLE.87
MANAGEMENT STRATEGIES FOR PREVENTION OF CV COMPLICATIONS IN SLE

Minimizing Framingham Risk Factors
In the future, it is likely that novel SLE-specific risk prediction panels will be developed
and validated for identification of high-risk patients who should be targeted with ther-
apeutic interventions to prevent CV complications. At present, expert panels in both
the United States and Europe recommend that patients with SLE should be annually
screened for traditional modifiable risk factors for CVD, including smoking status,
blood pressure, body mass index, diabetes, and serum lipids92,93; however, no ran-
domized clinical trials for the prevention of ATH in SLE exist to guide clinicians once
high-risk patients are identified.94 Our current screening and treatment strategies
are extrapolated from the best available evidence for the general population, with
some modifications for consideration of lupus-specific issues.
Hypertension: Antihypertensives
Because of the high relative risk for CV morbidity and mortality in SLE, it has been sug-
gested that SLE should be considered a cardiac risk equivalent similar to diabetes.95
Therefore, patients with SLE should be treated to the target blood pressure levels of
130/80, as recommended by the Joint National Committee (JNC 7) for those with other
high-risk comorbid conditions.36,96 No optimum SLE-specific antihypertensive medi-
cation regimen has been established97; however, angiotensin-converting enzyme
(ACE) inhibitors are generally the drugs of choice in patients with renal disease98
and are recommended as first-line therapy in patients with rheumatic disease by
the European League Against Rheumatism (EULAR) guidelines because of their po-
tential favorable effects on inflammatory markers and endothelial function.99 In addi-
tion, in one cross-sectional study, carotid ATH was associated with ACE inhibitor
nonuse.100 Angiotensin receptor blockers can also be considered in patients who
cannot tolerate ACE inhibitor therapy.101 Thiazide diuretics are recommended as first-
line therapy for hypertension in the general population by JNC 7 and would generally
also be a safe choice in subjects with SLE.36 Calcium channel blockers may be useful
in patients with coexisting Raynaud phenomenon or pulmonary hypertension but have
been associated in several cases with the development of subacute cutaneous
lupus.102 b-Blockers have been shown to precipitate Raynaud phenomenon103 and
thus should be used with caution in subjects with SLE.
Dyslipidemia: Statin Use

Statins are widely used in the general population to reduce CV morbidity.104–106 In
addition to their lipid lowering properties, statins have a variety of direct antiinflamma-
tory and immunomodulatory effects, including the diminished secretion of proinflam-
matory cytokines and chemokines.107–109 Statins also inhibit adhesion molecules,
reactive oxygen species formation, T-cell activation, and the upregulation of nitric ox-
ide synthesis.110 In an in vivo study of statins in a mouse model of SLE and ATH, the
gld.apoE / mouse, simvastatin therapy decreased atherosclerotic lesion area and
reduced lymphadenopathy, renal disease, and proinflammatory cytokine production,
even though it did not alter cholesterol levels.111
Although there is an abundance of data to support the use of statins in primary and
secondary prevention of ATH in the general population,104,112,113 the data in patients
with lupus have been much less consistent. In a recent small study of 21 patients with
SLE, statin use improved disease activity measured by SLAM-R scores at 6 months
but did not result in any changes in levels of potential cardiac biomarkers such
as TNF-a, vascular endothelial growth factor, IL-6, or soluble CD40 ligand
(sCD40L).114 In another small study of 60 patients with SLE, atorvastatin, 40 mg daily,
resulted in decreased lipid and CRP levels and slowed progression of coronary cal-
cium but demonstrated no change in myocardial perfusion defects compared with
placebo.115 In a trial of 33 patients with lupus postrenal transplant, those randomized
to fluvastatin therapy had a 73% reduction in cardiac events, although this difference
did not quite reach statistical significance (P 5 .06). Atorvastatin, 20 mg daily for
8 weeks, improved endothelium-dependent vasodilation in 64 women with SLE,
even after accounting for the presence of traditional cardiac risk factors.116 In the
largest trials conducted, however, the results were less promising. For example, in
a 2-year randomized controlled trial of atorvastatin, 40 mg daily, in 200 women
with SLE, statins did not significantly prevent progression of coronary calcium,
IMT or disease activity.117 Similarly, a randomized controlled trial of atorvastatin con-
ducted in 221 pediatric patients with SLE, the APPLE (Atherosclerosis Prevention in
Pediatric Lupus Erythematosus) trial, also demonstrated improvements in lipid levels
and hs-CRP levels but showed no significant impact on IMT progression.118 Many
trials that have demonstrated a preventive effect of statins in the general population
have larger sample sizes and a longer follow-up duration,119 so it is possible that
increased sample sizes and study lengths might have resulted in positive studies.
A secondary analysis of the APPLE trial did indicate that in pubertal patients with
SLE with high baseline hs-CRP levels, atorvastatin did decrease IMT progression.
This fact suggests that identification of high-risk patients for inclusion in clinical trials
may increase the likelihood that beneficial therapeutics will have positive trial results.
Further investigations are needed to clarify the role that statins could play in the pre-
vention of ATH in rheumatic disease populations. Until further studies are conducted
to determine the safety and efficacy of statin therapy in a broader population of pa-
tients with SLE, statin therapy should be limited to published guidelines such as the
National Cholesterol Education Panel.120
THE IMPACT OF MODULATORS OF LUPUS DISEASE ACTIVITY ON CVD

Antimalarial Therapy
Multiple retrospective cohort studies have demonstrated improved overall sur-
vival121,122 in patients with SLE treated with antimalarial agents. There is some
evidence to suggest that hydroxychloroquine may confer some protection by modu-
lating CV risk. For instance, antimalarials may have indirect cardioprotective benefits
by improving lipid profiles123,124 and improving glycemic control.125 There is also a
reduced incidence of thrombotic events in patients with SLE treated with antimalar-
ials.19,121,126,127 In 2 prospective lupus cohort studies, antimalarial use was associated
with a 50% to 60% decreased risk for CV events. Nonuse of hydroxychloroquine was
associated with higher aortic stiffness128 and plaque on carotid ultrasonography,42 2
subclinical measures of ATH. Although the exact mechanisms by which antimalarials
exert protection are not well understood, the recent understanding that hydroxychlor-
oquine is an antagonist of toll like receptor (TLR) 7 and 9 signaling is intriguing, given
the postulated roles of interferon-a in endothelial dysfunction and abnormal vascular
repair.129 Prospective randomized studies demonstrating a cardioprotective effect of
hydroxychloroquine in patients with SLE are needed.
Azathioprine
One retrospective case-control study of patients with SLE with documented CAD
found that patients with CAD were more likely to have been treated with azathio-
prine.130 Azathioprine use was also associated with cardiac events in the multiethnic
LUMINA cohort16 and with increased carotid IMT in the pediatric SLE APPLE cohort.38
Further studies will be needed to determine whether these associations are due to a
direct effect of azathioprine, confounding by indication (that is, patients treated with
azathioprine have more severe disease than the general lupus population), or the
inability of azathioprine to overcome the inflammation that leads to ATH.
Glucocorticoids
Glucocorticoid use may affect traditional cardiac risk factors such as hypertension,
obesity, and diabetes.131 In addition, prednisone doses greater than 10 mg/d have
been shown to independently predict hypercholesterolemia in SLE.132 Conflicting
data exist, however, regarding the overall risk of glucocorticoid therapy: both longer
duration of corticosteroid treatment32,83 and a higher accumulated corticosteroid
dose32,39,41,46,84 have been associated with a higher incidence of ATH in various co-
horts of patients with SLE. In the APPLE study of pediatric patients with lupus, how-
ever, the highest and lowest cumulative doses of corticosteroids were associated
with increased IMT, whereas moderate doses were associated with decreased IMT.
Roman and colleagues42 also found that former or current use of prednisone and
average dose of prednisone were significantly less in patients with carotid plaque,
implying that there may be a threshold dose at which the antiinflammatory effects of
glucocorticoids may be atheroprotective, whereas higher doses may be atherogenic.
Until such a threshold is determined, the authors recommend following the EULAR
recommendations that the lowest possible dose of corticosteroids be used in individ-
ual patients.99
Mycophenolate Mofetil
Mycophenolate mofetil (MMF) has several potential antiatherogenic effects. In ani-
mal models, MMF inhibits nicotinamide adenine dinucleotide phosphate oxidase,
thereby inhibiting oxidative stress.133 In patients with carotid artery stenosis,
2 weeks of MMF therapy resulted in increased numbers of regulatory T cells and

decreased plaque expression of inflammatory genes.101 In 2 separate animal
models of SLE and ATH, MMF treatment significantly reduced atherosclerotic
burden in addition to autoantibody circulation134 and recruitment of CD41 T cells
to atherosclerotic plaques.135 Studies in patients undergoing renal and cardiac
transplant have found decreases in ATH136 and CV mortality associated with myco-
phenolate use.137 A small prospective observational study from the authors’ group
of patients with SLE suggests that 12-week treatment with MMF and hydroxychlor-
oquine, but not azathioprine, results in significant improvement of piHDL function
(M.M. and B.S., unpublished data, 2013). In a recently published longitudinal SLE
cohort study, however, exposure of subjects to MMF was not associated with a
reduction of IMT or coronary calcium progression.138 Larger prospective studies
will need to be undertaken to clarify the potential role of MMF in prevention of pro-
gression of ATH in SLE.
CONSIDERATION FOR FUTURE CLINICAL TRIALS
As previously noted, no randomized clinical trials to date have positively identified a

successful therapeutic strategy for preventing CV morbidity in patients with SLE.
Unfortunately, there have been barriers to conducting such prevention trials. In
one recent randomized controlled pilot trial of CV-preventive medications in a Bos-
ton cohort, only 16.8% of eligible patients were willing to participate. Of the 41 pa-
tients who did enroll in the trial, over half dropped out within 6 months.97 Some
reasons for clinical trial nonparticipation and dropout included patient and treating
physician fears regarding placebo use, reluctance to add additional medications
to an already complicated medical regimen, and fear of changing treatment when
patients felt either too well or too ill.94 Future successful trials need to be designed
with these barriers in mind and will likely require extensive patient and physician
education.
In order to maximize clinical impact, future trials of lupus therapeutics should also
examine the effect of new medications on CVD. Although lengthy prospective longitu-
dinal studies that demonstrate a reduction in CV events may not be practical, demon-
stration of improvements in surrogate measures of ATH such as imaging modalities or
biomarkers could signal additional cardioprotective benefits for new lupus treatments.
In addition, examination of lupus-specific biomarkers could provide a more thorough
understanding of the CV impact of new drugs. For example, one drug recently
approved for rheumatoid arthritis, tocilizumab, was associated with increased mean
total and LDL cholesterol levels; however, it also altered the content of HDL choles-
terol toward an antiatherogenic phenotype (decreased HDL-associated serum amy-
loid A and increased PON) and decreased some (CRP, lipoprotein (a), D-dimer) but
not all other markers associated with cardiac risk.139 Although additional studies will
be needed to confirm that alterations in biomarkers and measures of subclinical
ATH can lead to improved patient outcomes, the goal of future lupus therapeutics
should be to develop treatments that both improve short-term disease activity and
decrease long-term comorbidities such as CVD.
In summary, the prevalence of ATH is higher in patients with SLE and occurs at
an earlier age. The lupus-related factors that account for this increased risk are
likely numerous and related to the factors described in this article. Identification
of at-risk subjects and increasing the understanding of pathogenesis of ATH in
SLE is critical to improve the quality of care and improve mortality in this vulnerable
population.
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Systemic Lupus
E r y t h e m a t o s u s an d
M a l i g n a n c i e s : A Review Article
Basile Tessier-Cloutier, MDa, Ann E. Clarke, MD, MScb,
Rosalind Ramsey-Goldman, MD, DrPhc, Caroline Gordon, MD
d
,
James E. Hansen, MDe, Sasha Bernatsky, MD, PhDa,*
KEYWORDS
Systemic lupus erythematosus Cancer Malignancy Epidemiology
KEY POINTS
Systemic lupus erythematosus (SLE) is associated with a small overall increased inci-
dence of malignancy, including a prominent (3-fold) increased risk of non-Hodgkin lym-
phoma (NHL), but a marked decreased risk of other malignancies (such as breast cancer).
Although NHL is increased 3-fold in SLE, it is still a rare event (about 1 event in 2000
person-years of follow-up, or <1% of patients followed long term).
Inadequate viral clearance in SLE could promote the development of certain malignancies
such as cervical cancer.
To date, the evidence does not clearly point toward inherent SLE activity as a risk factor
for cancer, although more research is needed. Regarding drugs and cancer risk, there are
trends in the data suggesting that cyclophosphamide may be a risk factor for later hema-
tological cancers in SLE, but even this drug exposure does not explain most of the altered
cancer risk profile in SLE.
Cancer preventive methods such as smoking cessation and regular cancer screening (eg,
for cervical and breast malignancies) are important in the SLE population.
Disclosure: None.
a
Division of Clinical Epidemiology, McGill University Health Centre, 687 Pine Avenue, V Build-
ing, Montreal, Quebec H3A 1A1, Canada; b Division of Rheumatology, University of Calgary,
3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada; c Division of Rheumatology,
Northwestern University Feinberg School of Medicine, McGaw Pavilion, 240 East Huron Street,
Suite M-300, Chicago, IL 60611, USA; d Division of Rheumatology, College of Medical and
Dental Sciences, University of Birmingham, Edgbaston B15 2TT, UK; e Department of Therapeu-
tic Radiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
* Corresponding author. Division of Clinical Epidemiology, Research Institute of the McGill
University Health Centre, 687 Pine Avenue West, V Building, Room V2.09, Montreal, Quebec
H3A 1A1, Canada.
E-mail address: sasha.bernatsky@mcgill.ca

498 Tessier-Cloutier et al
INTRODUCTION
Systemic lupus erythematosus (SLE), an autoimmune disorder with complex environ-

mental and genetic interactions, affects approximately 1 in 1000 women in North
America.1 In the last 5 decades, advances in management have improved 5-year sur-
vival to more than 90%.2 The longer survival translates, in some cases, to considerable
long-term morbidity, including distinct cancer risk profiles.
For more than a decade, autoimmune disorders such as SLE have been associated
with an increased cancer risk, particularly for certain cancer types.3 However, the un-
derlying pathophysiologic mechanisms are still not fully understood. In SLE, the pro-
posed pathways currently include a possible link with medications, inherent immune
system abnormalities,4 an overlap with clinical syndromes such as Sjögren,5 viral in-
fections, as well as traditional lifestyle cancer risk factors.6 The most recent evidence
shows a slight (standard incidence ratio [SIR], 1.14; 95% confidence interval [CI],
1.05–1.23) increase in cancer risk overall.7 However, considerable variation between
specific cancer subtypes occurs within these data. The risk of hematologic cancers,
especially non-Hodgkin lymphoma (NHL), is increased about 3-fold,7–10 although
breast, endometrial, and possibly prostate and ovarian cancers seem to be associated
with a decreased risk in the SLE population.7,11,12
HEMATOLOGIC CANCERS
An increased incidence of hematologic malignancies in the SLE population was

initially suggested more than 3 decades ago13 and has now been supported by
many studies.8–10,14 Based on incidence and mortality data generated from the large,
multicentre, international SLE cohort contributed by Systemic Lupus International
Collaborating Clinics (SLICC) and other investigators, it was observed that NHL inci-
dence (SIR, 3.02; 95% CI, 2.48–3.63) and mortality (standardized mortality ratio
[SMR], 2.8; 95% CI, 1.2–5.6) risks were particularly increased in patients with SLE,
compared with expected general population cancer rates.7,15 Further studies identi-
fied an increased risk for Hodgkin lymphomas (HL)16,17 and leukemia7–9 in patients
with SLE. One study18 suggests that the risk of developing multiple myeloma might
also be increased in patients with SLE, but additional studies are required to confirm
this association.
Genetic changes, such as the t(14:18) translocation (which results in overexpression
of BCL2 caused by juxtaposition of the BCL2 gene next to an immunoglobulin gene)
have been linked to lymphoma development.19 In addition, a polymorphism involving
the interleukin (IL)-1 receptor antagonist has been noted to be significantly overex-
pressed in a group of patients with secondary acute myeloid leukemia.20
SLE activity has been invoked as a potential factor to explain the increased lym-
phoma risk in SLE. Although increased disease activity has been associated with
higher cancer risk in certain autoimmune disorders (for example, in rheumatoid
arthritis [RA], higher disease activity was shown to be a marker of lymphoma risk, in
one study),21 the immune system is also responsible for targeting abnormal cells.22,23
Thus, the effects of disease activity in one rheumatic disease, such as RA, may be
different in another, such as SLE. Case-cohort analyses of lymphoma cases in the
large international multicentre SLE cohort revealed no clear relationship between dis-
ease activity and lymphoma risk (hazard ratio [HR], 0.68; 95% CI, 0.36–1.29).24,25
Diffuse large B-cell lymphoma (DLBCL) is the most increased subtype of lymphoma
in SLE.16 DLBCL lesions arise from activated lymphocytes, the cell line responsible for
most of the inflammation in autoimmune disorders such as SLE, which suggests that
the chronic inflammatory state seen in patients with SLE contributes to the cancer risk
Systemic Lupus Erythematosus and Malignancies 499
profile in SLE. Furthermore, DLBCL lesions that develop in patients with SLE seem to
highly express APRIL (a proliferation-inducing ligand), a cytokine from the tumor ne-
crosis factor (TNF) ligand superfamily that is essential for B-cell survival and develop-
ment.4 The investigators of that study proposed that the overproduction of APRIL
might mediate the development of lymphoma in SLE and other rheumatic diseases.
The mechanism by which APRIL induces lymphoma is unclear, but it seems to play
a role in allowing NHL B cells to escape apoptosis.26
The Epstein-Barr virus (EBV) is suggested to have a role in the pathophysiology of
SLE,27–29 and may also contribute to the increased risk of malignancy in SLE. EBV
seropositivity is only slightly increased in patients with SLE compared with the general
population, but some data indicate altered ability to clear this viral infection in SLE.30
Increased viral load, EBV mRNA expression, EBV-directed antibodies, and decreased
EBV-directed cell immunity have all been shown in patients with SLE compared with
healthy controls.28,30 This finding is relevant to studies of the association of SLE and
cancer because EBV has been associated with malignancies in certain populations.
For example, EBV is associated with neoplastic processes such as Burkitt lymphoma,
Hodgkin disease, immunosuppression-related DLBCL, and nasopharyngeal and
gastric carcinomas.31 In addition, EBV viral load was shown to be prognostic of
impending lymphoproliferative disorder in transplant recipients.32 The mechanism
by which EBV is thought to promote malignancy seems to involve B-cell immortaliza-
tion, manipulating host chromatin-remodeling machinery, and promoting cell migra-
tion and resistance to apoptosis through p53 blc-2 A20 and Fas modulation.31,33
Polymorphism of the Fas gene and an epistatic relationship between Fas and Sle1
genes has been reported in the SLE population34–39 and altered Fas-mediated
apoptosis contributes to the pathophysiology of autoimmune lymphoproliferative syn-
drome (ALPS). ALPS is a rare, autosomal dominant, inherited genetic disorder that in-
volves defective apoptosis of lymphocytes and subsequent increased risk of
developing both autoimmunity (including many SLE manifestations: rashes, nephritis,
arthritis, and autoantibodies) and lymphomas. Thus, the family history of affected per-
sons features multiple manifestations of both autoimmune disease and lymphoma.
The exact prevalence of ALPS is uncertain, but about 100 affected individuals have
been documented worldwide. Although this condition is an example of how a genetic
defect can increase an individual’s risk for both SLE and lymphoma, this specific auto-
somal dominant inherited genetic disorder is too rare to explain most of the lymphoma
cases that arise in SLE.
In addition, a link between primary Sjögren syndrome and lymphoma has been
shown in many studies,3 and it has thus been suggested that lupus-induced second-
ary Sjögren syndrome could account for the heightened risk of hematologic malig-
nancies. Our case-cohort analyses based on the large multicentre international SLE
cohort showed a trend supporting an increased risk for lymphoma development in pa-
tients with Sjögren syndrome (HR, 1.79; 95% CI, 0.88–3.62).24 Here, Sjögren syn-
drome was based on clinical judgment, as opposed to requiring patients to fulfill
specific criteria, and thus may have been subject to nondifferential misclassification
of the exposure, which could have biased this result toward the null value. Thus, it re-
mains possible that secondary Sjögren syndrome may explain some (but not all) of the
increased lymphoma risk in SLE.
There continues to be great interest in the potential role of medications in mediating
lymphoma risk in SLE. Case-cohort analysis of the multicentre international SLE
cohort suggested an increased risk of lymphoma in subjects exposed to cyclophos-
phamide (SIR, 2.80; 95% CI, 0.87–8.98) as well as to cumulative glucocorticoids
(SIR, 2.57; 95% CI, 0.94–7.04) compared with SLE controls without cancer. The
mechanism of cyclophosphamide’s effects in increasing cancer risk might be direct,

such as through its immunosuppression and cytotoxic properties, or indirect, through,
for example, promoting the emergence of oncogenic virus (eg, EBV or human papil-
loma virus [HPV]).
LUNG CANCERS
Lung cancer also has a reported increased incidence (SIR, 1.30; 95% CI, 1.04–1.60)7,9
and mortality (SMR, 2.3; 95% CI, 1.6–3.0)15 in the SLE population. Although a potential
trend toward overrepresentation of rarer types (including bronchoalveolar and carci-
noid) was identified in one study, the overall histologic distribution was comparable
with that of the general population.40
Genetic associations are an interesting possible explanation for the association
between SLE and lung cancer, because there is evidence of shared susceptibility
loci (4p15.1–15.3 and 6p21).40 Although the idea of a genetic link predisposing to
both lung cancer and SLE is plausible, it remains premature and thus this represents
an area for future research.
The proven link between lung cancer, fibrosis, and inflammation41 has also led to the
consideration of pulmonary involvement (that is, alveolitis and/or fibrosis) in SLE as
playing a direct role in lung cancer risk. However, in our large, multicentre, interna-
tional SLE cohort, clear documentation of preexisting pulmonary damage was
reported in only 1 lung case; however, more prospective analyses are warranted.
Smoking may represent a shared environmental risk factor between both lung can-
cer and SLE. Data support an association between lupus and smoking,42 which might
contribute to the reported increased lung cancer incidence in SLE. Case-cohort ana-
lyses have strongly suggested smoking as an important predictor of lung cancer in
SLE.43 In addition, only 20% of patients affected by lung cancer from the large inter-
national SLE cohort had previously been exposed to immunotherapy40; this may sug-
gest that drugs are not the primary cause of lung cancer in patients with SLE.
CERVICAL CANCERS AND DYSPLASIA
It has been suggested that women with SLE are at an increased risk for invasive cervical
cancer and for cervical dysplasia44; however, not all analyses to date have been defin-
itive.45 The multicentre international SLE cohort, which excluded cervical dysplasia and
carcinoma in situ, was unable to document an increased risk of invasive cervical cancer
in SLE, although a trend was evident (SIR, 1.27; 95% CI, 0.78–1.93). The low incidence
of cervical cancer (about 6.6 per 100,000 North American women) makes it a challenge
to assess its relation to SLE with sufficient power. There may also be ascertainment is-
sues, because cancer registries often do not record noninvasive malignancies.
Nevertheless, the suggested increase in incidence in cervical cancer in SLE is
particularly interesting from a pathophysiologic standpoint. There is growing evidence
for increased rates of HPV (the infection responsible for cervical cancer), including its
high-risk aggressive variants, in women with SLE.46,47 Moreover, exposure to immu-
nosuppressant medications (especially cyclophosphamide, and possibly azathio-
prine) in SLE has also been shown to increase susceptibility to high-risk HPV
infection, overall HPV infection, and cervical dysplasia.48–50 Thus, although a direct
link has yet to be found, based on this evidence and the strong association that has
been repeatedly shown between cervical HPV infection and malignant transformation,
female patients with SLE are likely to be at increased risk for cervical cancer.
As with cervical carcinoma, the risk of other malignancies that are also strongly
associated with HPV is increased in SLE. The most up-to-date analyses argue for
an increased risk in vulvar carcinoma (SIR, 3.78; 95% CI, 1.52–7.78) with strong trends
for an increased risk also for vaginal (SIR, 3.80; 95% CI, 0.46–13.74) as well as anal
carcinoma (SIR, 26.9; 95% CI, 8.7–83.4).7,51 Although these results are supported
by other investigators (Dreyer and colleagues51), the low absolute number of these
rare malignancies should be kept in mind. It has been suggested by some clinicians
that the increased incidence of these cancer types in SLE could also be accounted
for by inadequate viral clearance. Iatrogenic immunosuppression and genetic and
innate immunity defects in lupus are possible mechanisms.50,52
Routine screening for cervical dysplasia is important for patients with SLE. How-
ever, one study observed that female patients with SLE with the most severe disease
burden (based on SLICC/American College of Rheumatology damage index scores)
were the least likely to have undergone cervical screening.53 The explanation is likely
multifactorial but it argues for the importance of counseling adherence to national cer-
vical screening protocols and guidelines.
HEAD AND NECK CANCERS
A recent study54 suggested that patients with SLE are at increased risk for head and
neck malignancies. A significantly high incidence rate ratio of 2.16 (95% CI, 1.13–4.13)
was reported,54 which is consistent with previous data.55 However, both of these
studies were in Asian populations (which have a higher general population risk for
head and neck malignancy), therefore the relevance of these data to North American
and European SLE populations is less certain. The investigators of these two studies
suggested that defective immune surveillance related to downregulated cytotoxic
T-lymphocyte populations in patients with SLE might be responsible for the increased
head and neck malignancy incidence, but their data cannot be used to prove this hy-
pothesis. Altered clearance of oncogenic viruses in SLE is also an important potential
consideration, because head and neck malignancies may be associated with HPV56
and potentially, in some immunosuppressed individuals, EBV.57–59
DECREASED CANCER RISK IN SLE
Recent data have revealed that some cancers present with a decreased incidence rate
in the SLE population, as is the case for breast (SIR, 0.73; 95% CI, 0.61–0.88), endo-
metrial (SIR, 0.44; 95% CI, 0.23–0.77), and possibly prostate (SIR, 0.65; 95% CI, 0.32,
1.16) and ovarian (SIR, 0.64; 95% CI, 0.34, 1.10) cancers.7,11,12 This observation sug-
gests a complex interplay of risk and protective mechanisms possibly linking the im-
mune and endocrine systems to cancer risk in SLE.
First, because these (especially breast and endometrial) cancers are often driven by
hormonal factors, it has been suggested that, if the metabolism of estrogen or other
predominantly female hormones is altered in SLE, this could slow the progression
of some cancers. When stratifying patients with SLE according to age (<50 years,
and 50 years), both groups had a decreased breast cancer incidence; it is antici-
pated that, if hormonal factors were mediating this decreased risk, it would only be
observed in the premenopausal ages. There is also speculation regarding a possible
protective role of certain medications used in treating patients with SLE, such as an-
timalarials, in long-term cancer risk.60 The proposed mechanism involves its role on
promoting the autophagy of certain malignant cells.61,62 However, there are as yet
no robust data linking these drugs to a decreased risk of certain cancers in SLE.63
A well-done study of a large cohort of patients with RA assembled from administrative
data showed no decrease in cancer risk related to antimalarial drug use.64
In addition, aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) have been

linked with decreased risk of lung and potentially other cancer.65,66 However, there
is at present no robust evidence that points to a clear effect of aspirin and NSAIDs
in cancer risk in SLE.
It is possible that the decreased risk of certain cancers in SLE is genetically medi-
ated. However, we analyzed a large breast cancer genome-wide association study
dataset and did not observe any differences in the frequency of 10 SLE-related sin-
gle-nucleotide polymorphisms in breast cancer cases (in the general population)
compared with cancer-free controls. If decreased breast cancer risk in SLE is influ-
enced by genetic profiles, this may be caused by complex interactions and/or epige-
netic factors.67
Another potential explanation for the decreased risk of breast cancer in women with
SLE is that lupus autoantibodies may be suppressing the emergence of certain types
of malignant cells. A cell-penetrating, lupus-related, anti-DNA antibody was shown to
inhibit DNA repair and to be toxic to cancer cells with intrinsic defects in DNA repair.68
Triple-negative breast cancers (that is, breast cancers that do not express estrogen,
progesterone, and HER2 receptors) are known to harbor defects in DNA repair and
thus are likely to be particularly susceptible to the effects of such lupus autoanti-
bodies, and it is possible that suppression of the emergence of triple-negative and
BRCA-deficient breast cancers by lupus anti-DNA antibodies may account in part
for the lower-than-expected rates of breast cancer in women with SLE. This line of
reasoning is supported by a trend for decreased ductal carcinoma, predominantly tri-
ple negative,69 in the SLICC cohort.70
Regulatory T cells (Tregs) may also play a role in suppressing the development of
breast cancer in SLE. Tregs are responsible for attenuating immune responses and
in some cases may protect malignant cells from the immune system’s role in deleting
abnormal cancer cells, such as breast cancers. Tregs that are highly expressed in
some breast tumors in patients who do not have lupus are associated with a poor
prognosis.71 However, because Treg functions are altered in SLE, it is possible that
this favors a more effective antitumor response (in SLE) from unopposed helper
T cells. Thus, in a disease as complex as SLE, opposing forces, for and against ma-
lignant development, could also be responsible for the equivocal data to date,
regarding whether or not SLE disease activity is, in itself, a factor that alters cancer
risk.
SUMMARY
Data published in the last decade have provided information on the association be-
tween lupus and malignancy. To date, the evidence does not clearly support SLE ac-
tivity as a risk factor for cancer, although studies performed to date are few. The data
regarding the relationship between medications used to treat SLE and cancer risk sug-
gest that cyclophosphamide may be a risk factor for later hematological cancers in
SLE, but even this drug exposure does not fully explain the altered cancer risk profile
in SLE. The role for genomic alterations in relation to drug metabolism and the possible
mechanism of SLE-related cell-penetrating anti-DNA antibodies in suppression of
breast cancer in SLE are useful directions for future research.
At present, promotion of preventive measures such as smoking cessation and
encouraging regular screening programs for cervical and breast cancer are
common-sense interventions that should be part of the management of patients
with SLE. In addition, because cyclophosphamide remains an essential therapy for se-
vere forms of SLE involvement, and has other significant adverse events, there is a
need for development of more effective and safer lupus drugs while continuing pro-
spective studies addressing the risk factors for cancer in patients with lupus.
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Post-marketing
Experiences with
B el im u ma b i n t h e Tre atm en t o f
SLE Patients
Anca D. Askanase, MD, MPHa,*, Jinoos Yazdany, MD, MPH
b
,
Charles T. Molta, MDc
KEYWORDS
SLE Lupus Belimumab Observational studies
KEY POINTS
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple
organ systems and whose hallmark is the production of autoantibodies.
Belimumab appears to be efficacious in the treatment of SLE.
Response rate to belimumab is approximately 50%.
No safety signals were noted and no significant side effects were reported to belimumab.
INTRODUCTION
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multi-
ple organ systems and whose hallmark is the production of autoantibodies.1–3 A diag-
nosis of SLE relies on the American College of Rheumatology (ACR) criteria; the
presence of 4 out of 11 criteria is diagnostic.4–6 About 300,000 to 4 million people suf-
fer from SLE in the United States.7 Two recent studies based on population data spon-
sored by the Centers for Disease Control and Prevention and local state health
departments calculated a prevalence of 73 cases per 100,000.8,9 SLE treatments
that include antimalarials, nonsteroidal antiinflammatory drugs (NSAIDs), corticoste-
roids (CS), cytotoxics, and immune suppressants improve disease activity in SLE
Disclosure Statement: Consultant and Speaker Bureau for GSK (A.D. Askanase); GSK employee
(C.T. Molta).
a
Department of Medicine, Columbia University Medical Center, 630 West 168th Street, P&S
10-508, New York, NY 10032, USA; b Department of Medicine, University of California, San
Francisco, School of Medicine, 1001 Potrero Avenue, SFGH 30, San Francisco, CA 94143, USA;
c
GlaxoSmithKline, 5 Crescent Drive, Philadelphia, PA 10112, USA
E-mail address: ada20@columbia.edu

508 Askanase et al
patients but put patients at risk for long-term sequelae of low level, active SLE as well
as potential serious side effects from the medications.10,11 In addition, some patients
still develop flares despite what seems to be optimal treatment, and these flares may
contribute to the need for increased CS use and subsequent long-term damage.5
Therefore, there continues to be a need for new therapeutic options, more effective
and safer therapies for SLE.
Normally, B cells play an essential role in maintaining a functional immune system:
they produce antibodies, serve as antigen-presenting cells, and secrete proinflamma-
tory cytokines in response to foreign antigens.12 In the pathogenesis of SLE, however,
an increasingly large proportion of B cells fail to distinguish foreign and self-antigens
and produce antibodies that target self-antigens, leading to an overreactive immune
response.12 B-lymphocyte stimulator (BLyS), a proliferation and survival factor of B
cells, is also known as the B-cell activating factor (BAFF).13 Studies showed an asso-
ciation between BLyS and SLE. SLE patients had significantly greater levels of plasma
soluble BLyS than healthy controls or patients with rheumatoid arthritis; circulating
BLyS levels were also found to correlate with SLE disease activity measured by the
Selena SLEDAI (SS) score.14,15 These studies suggested that BLyS is a valid treatment
target in SLE.
Belimumab (Benlysta) is a human recombinant monoclonal antibody that targets
and inhibits soluble BLyS. The binding between belimumab and BLyS prevents the
latter from attaching to its receptor on B cells, leading to apoptosis and reduction of
circulating B-cell clones. This BLyS–anti-BlyS structure is subsequently cleared by
the immune system.13,16 BLyS clinical trials showed that belimumab plus standard
SLE treatment reduces peripheral B-cell levels and improves disease activity in
some SLE patients. Based on data released to investors by GlaxoSmithKline (GSK),
more than 15,000 patients have received at least one infusion of belimumab in the
United States. Considering the approximate number of lupus patients to be
300,000, it follows that about 5% of all lupus patients are treated with belimumab.8,9
Belimumab treatment is not appropriate for patients with mild SLE; the percentage of
belimumab-treated lupus patients among those who would benefit from such treat-
ment can be estimated to be higher.
To further understand the clinical application of belimumab in treating SLE, this
article discusses the registration studies and post-marketing experiences and the clin-
ical outcomes of belimumab treatment.
REGISTRATION STUDIES
To evaluate the safety and biologic activity of belimumab, a randomized, multicenter,

double-blind, placebo-controlled study (phase I) was conducted in 70 patients with
stable mild/moderate SLE disease activity for at least 2 months before screening,
with measurable SLE-related autoantibodies, and on a stable treatment regimen of
immunosuppressant, antimalarials, NSAIDS, and low-dose CS (15 mg prednisone).
Four escalating doses of intravenous belimumab (1.0, 4.0, 10, or 20 mg/kg) plus
standard of care (SOC) were tested and compared with placebo in 8 cohorts.
Cohorts1 to 4 received one single infusion of placebo or belimumab, whereas Cohorts
5 to 8 received 2 identical infusions of placebo or belimumab with the second one
administrated after 3 weeks of receiving the first dose. Of the 70 patients, 13 received
placebo and 57 received belimumab. Data on adverse events (AEs)/serious AEs, SLE
disease activity, hematologic changes, serum belimumab concentrations, and periph-
eral B-cell counts were evaluated at 84 days and 105 days after the last infusion. Both
the placebo and belimumab groups had similar incidence of AEs. Belimumab-treated
Belimumab in the Treatment of SLE Patients 509
patients in single- and double-dose cohorts had a significant reduction of peripheral B

cells and reduced serum immunoglobulin level, compared with the placebo group.
These data suggested that belimumab was well tolerated and effectively reduced pe-
ripheral B-cell counts in patients with SLE.16,17
To further evaluate the safety and efficacy of adding belimumab to SOC, a double-
blind, placebo-controlled, randomized, dose-ranging study (phase II) was conducted
in 449 patients with active SLE. Patients had to have a diagnosis of SLE based on the
following ACR criteria: an SS score greater than or equal to 4 at screening, a history of
measurable SLE-related autoantibodies, and a stable treatment regimen of immuno-
suppressant, antimalarials, NSAIDs, and/or CSs. Eligible patients were stratified
based on their screening SS score (4–7 vs 8). In addition to SOC SLE medications, pa-
tients received infusions of 1, 4, or 10 mg/kg belimumab or placebo at days 0, 14, and
28, and every 28 days thereafter for 52 weeks. Data on Physician Global Assessment
(PGA), SS scores, the SELENA-SLEDAI flare index (SFI), British Isles Lupus Assess-
ment Group index (BILAG), and hematological and immunologic variables were
collected and compared between baseline, week 24 and 52. The change in the SS
score by week 24 and time to first flare during the study period were the 2 primary end-
points, whereas the changes in SS and BILAG scores between week 24 and 52, CS
doses, and immunologic parameters were secondary endpoints.18
The changes in SS scores, in a dose-independent manner across belimumab treat-
ment groups, were similar between placebo and individual treatment groups at 24 and
52 weeks. Although no significant difference was observed in the time to first flare over
the study duration, the time to first flare and the rate of severe flares during 24 to
52 weeks differed significantly between the treatment and placebo groups (154 vs
108 days; 12 vs 17%, respectively). Also, belimumab treatment groups had a signifi-
cant reduction in prednisone dose ( 19.9%) between 38 and 52 weeks when
compared with the placebo group ( 11.7%), especially in patients who received
10 mg/kg belimumab ( 40.5%). Starting at week 4, significant improvement in PGA
scores was noted in all treatment groups ( 31%) compared with the placebo group
( 14%), with the most improvement observed in the 10 mg/kg belimumab group.
The belimumab and placebo groups had similar rates of AEs. Despite the fact that
the primary endpoints were not met, these results supported the biologic activity
and safety of belimumab and allowed for a better understanding of the pharmacody-
namics of belimumab, SLE disease activity, and clinical trial design. The modifications
to study design suggested by these groups include the following: (1) despite the early
improvements in B-cell, PGA score reduction suggested that a longer study period
was needed for clinical benefits to be reflected in SS and SFI scores; (2) it was noted
that 71.5% of the cohort had a positive antinuclear antibodies and/or dsDNA at
baseline, and a subset analysis showed that serologically active patients responded
to belimumab more effectively than serologically negative patients; (3) changes in
concomitant medications could also confound the efficacy of belimumab; (4) given
the heterogeneity of SLE, the use of dichotomous measures such as the SS and
BILAG was not able to fully capture the partial changes in disease activity. Based
on data from the earlier trial, the SLE Responder Index (SRI), a novel outcome mea-
sure, was developed to better assess the efficacy of belimumab in SLE patients.
The SRI was defined as a combination of a minimum 4 points reduction in SS score,
either no new BILAG A or 2 new BILAG Bs, and a maximum 0.3 point increase in PGA
score from baseline.18,19
To understand the long-term effects of belimumab on B cells, 21 patients from this
clinical trial enrolled in a substudy and received their previous dose or 10 mg/kg of
belimumab plus SOC every 28 days for 80 weeks. Patients could subsequently roll
510 Askanase et al
over into an open-label mechanistic extension study and receive 10 mg/kg belimu-
mab. Blood samples were collected on days 0, 84, 168, and every 180 days thereafter;
data on 17 patients were available for analysis. This extension study further confirmed
the critical role of BLyS in B-cell survival and that belimumab reduced circulating naı̈ve
B cells.20
The long-term safety and efficacy data were recently evaluated in 296 patients who
entered the phase II continuation study over 7 years. Of 177 patients who remained in
the study after 7 years, 135 initially had positive serologies. Patients had sustained
improvement in disease activity, decreased flares, and reductions in autoantibodies
and CSs, indicating stable efficacy over time. Seven deaths were observed with no
cause predominating. The safety of long-term belimumab treatment was reassuring
and similar to the safety profile reported in the same cohort at the 4-year follow-
up.21,22
BLISS-52 and BLISS-76 were 2 multicenter, randomized, placebo-controlled, clin-
ical trials conducted in different geographic sites to assess the safety and efficacy of
belimumab plus SOC in patients with active SLE (phase III). To participate in the
studies, patients had to be seropositive at screening and baseline, receive a stable
SLE treatment regimen, meet at least 4 of the 11 ACR criteria, and have an SS score
greater than or equal to 6 at screening. In addition to SOC, both studies randomized
patients to receive infusions of 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo
on days 0, 14, 28, and every 28 days thereafter. The primary efficacy endpoint was the
change from baseline in SRI at 52 weeks. Secondary endpoints included a minimum 4
points reduction in SS score at 52 weeks, improvements in PGA and Short Form-36 at
24 weeks, and tapering in prednisone dose by at least 25% from baseline and to less
than or equal to 7.5 mg/d during 40 to 52 weeks. Differences between groups were
noted starting at week 16 in the 10 mg/kg belimumab group and week 38 in the
1 mg/kg group.23,24
Eight hundred sixty-seven patients from Eastern Europe, Asia, and Latin America
were enrolled in BLISS-52 and received SOC plus belimumab or placebo for 52 weeks.
The primary endpoint of the study was met: both the 1 mg/kg (51%) and 10 mg/kg
(58%) belimumab groups had significantly higher SRI response rates than the placebo
group (44%) at 52 weeks. BLISS-76 included 819 patients from the Europe and North
America, who were followed for 76 weeks. This study also met its primary endpoint:
both the 1 mg/kg (40.6%) and10 mg/kg (43.2%) belimumab groups had higher percent
responders than the placebo group (33.5%), with the only latter being statistically sig-
nificant at 52 weeks. Exploratory endpoints analysis in BLISS-52 and BLIS-76 showed
that both belimumab plus SOC treatment groups had significantly reduced rate of dis-
ease flares, increased time to the first flare, no worsening in PGA scores, tapered
prednisone dose, and decreased serologic activity when compared with the placebo
(SOC) group. Based on the data collected from these 2 clinical trials, it was suggested
that patients with greater disease activity, lower complement, higher anti-dsDNA
levels and current prednisone use have greater therapeutic benefits from belimumab
treatment.25 Overall, these 2 clinical trials confirmed the safety and efficacy of belimu-
mab in treating SLE. No significant differences in safety signals were noted between
the groups.23,24
METHOD
This article discusses the available post-marketing experiences with belimumab. Data
from 3 recently published abstracts presented at the 2013 American College of
Rheumatology Annual Meeting will be discussed. These abstracts containing data
from 3 observational studies, one based on data collected from a lupus registry and
the others from academic and clinical practices, examined the safety and efficacy
of belimumab in treating SLE patients and shed light on the use of belimumab in the
clinical care of lupus patients.
RESULTS
Post-approval Observational Results
Favorable clinical response to belimumab at 3 months
The clinical responses of 115 belimumab-treated SLE lupus patients from academic
SLE clinical practices were analyzed to evaluate the efficacy and use of belimumab
plus standard SLE care. A nonvalidated clinical response was defined here as a
greater than or equal to 50% reduction in investigator’s impression in addition to no
worsening in other organ systems. Of the 16 experienced clinical researchers invited
to participate in this observational study, 9 participated and completed a question-
naire for each patient on belimumab. Information on demographics, SLE data, and
belimumab were collected. A total of 151 questionnaires were returned. Demo-
graphics and SLE characteristics are presented in Table 1. Table 2 summarizes the
clinical outcomes in all three studies. Data on 115 patients who received belimumab
for at least 3 months were analyzed. Seventy-nine of 115 patients received belimumab
for at least 6 months. Arthritis (73.5%), rash (51.0%), and serositis (17.2%) were the
most common clinical manifestations requiring treatment with belimumab, followed
by inability to taper CSs (20.5%). By 3 months, 55 (47.8%) patients clinically
responded and improved notably in either or both arthritis and rash. By 6 months,
46 (58.2%) clinically responded and improved in arthritis, rash and/or nephritis.
Patients with renal disease were treated with belimumab and had a remarkably high
clinical response rate: 4 of 5 (80%) by 3 months and 2 of 3 (66.7%) by 6 months.
Belimumab was discontinued in 20 (13.2%) patients for various reasons: central
Table 1
Summary of demographic characteristics and SLE treatment from 3 post-marketing studies of
belimumab
Askanase et al,2 2013 Collins et al,3 2013 Yazdany et al,1 2013

Age (y) 43.1 41.8 39.1
Gender (%)
Female 92.1 89.8 94
Disease Duration (y) 12.9 N/A 10.7
Race/Ethnicity (%)
White 69.7 51.6 41
Black 21.2 25.5 47
Hispanic 4.5 16.7 12
Asian 6.1 N/A N/A
Others N/A 6.3 N/A
SLE Medications (%)
Prednisone equivalent 70.9 77.3 82
Azathioprine 21.9 N/A 27
Mycophenolate mofetil 37.1 N/A 31
Methotrexate 13.2 N/A 15
Antimalarial 71.5 N/A 75
512
Askanase et al
Table 2
Clinical outcomes
% Responder (# of Patients
at Time Point) Discont. Adverse
Paper N Dominant Manifestations (%) Primary Instrument 3 6 12 N (%) Events N (%)
Askanase et al,2 2013 151 Arthritis (73.5) Investigator’s impression of 47.8 (115) 58.2 (79) N/A 20 (13.2) 14 (9.3)
Mucocutaneous disease (51.0) 50% improvement
Serositis (17.2)
Collins et al,3 2013 384 N/A Physician impression of N/A 47.1 30.2 43 (11.2) 8 (18.6)
50% improvement
Yazdany et al,1 2013 68 Arthritis (52) SS N/A N/A N/A 18 (26.5) 4 (5.9)
Mucocutaneous disease (19) PGA
Serositis (8)
nervous system (CNS) lupus (3), myocardial infarction (1), losses of insurance (3),
infection (3), infusion reactions (3), severe arthritis flare (1), stroke-line symptoms (1),
worsening neuropsychiatric condition (1), worsening myositis (1), elective surgery
(1), and no clinical response (2). This study showed the efficacy of belimumab was
consistent with the results from previous published clinical trials and similarly effective
across all ethnic groups.2
Twelve-month outcomes associated with belimumab in patients with systemic lupus
erythematosus in clinical practice settings: the OBSErve study
A total of 501 patients followed by 60 community rheumatologists for 24 months were
evaluated in this retrospective, multicenter charter view. At 12 months, 384 adult SLE
patients, who had received more than 8 infusions of belimumab, were randomly iden-
tified and followed. Demographics, physician impression of disease activity, disease
characteristics, and concomitant medications were collected 6 months before (base-
line) and 6 and 12 months after initiation of belimumab treatment. Demographics and
SLE treatment are presented in Table 1. Physician’s impression of change in SLE
disease manifestations was the primary outcome measure and was defined by a non-
validated physician described response of 20%, 50%, and 80% improvement for each
6-month study period. The change in physician’s impression was measured by looking
back at the previous 6-month study period (see Table 2). Between 0 and 6 months,
47.1% of patients showed more than or equal to 50% improvement based on physi-
cian’s impression. A small percentage (0.5%) of patients had no improvement, and
0.5%worsened. At 12 months, 30.2% of patients demonstrated more than or equal
to 50% improvement compared with their condition at 6 months, whereas 9.9% of
patients were the same and 3% worsened. Of 297 (77.3%) CS users at baseline,
104 (35%) tapered and discontinued CSs at 12 months. Among the patients who
received CSs, the mean CS dose changed from 19.4 mg/d at baseline to 8.4 mg/d
at 12 months. However, 6 patients started CS treatment during this study frame.
For those subjects with recorded scores (N 5 93), there was a 59.2% reduction in
SS scores (12.5 vs 5.1), 58.7% reduction in PGA scores, 61.5% improvement in
Patient Global Assessment scale scores at 12 months compared with baseline.
Fourty-three (11.2%) patients discontinued belimumab between 6 and 12 months:
37.2% patient request, 27.9% medication not effective, 20.9% lack of patient compli-
ance, 18.6% disease progression, 7% loss of insurance/reimbursement, and 7% loss
to follow-up or death. Safety was not assessed in this study. Overall, this study sug-
gested that incorporating 10 mg/kg of belimumab into SLE therapies for more than
12 months produced favorable clinical outcomes and allowed for tapering of CS.3
Post-marketing experience with belimumab in US lupus centers: data from the Lupus
Clinical Trials Consortium, Inc. (LCTC) national patient registry
The study followed a cohort of 1189 SLE patients from 15 participating US lupus
centers for an average of 23.2 months. From this cohort, 68 patients (5.7%) received
belimumab; in this subset, the study observed clinical indications, characteristics of
patients, side effects, and reasons for discontinuations. Patients who received at least
one dose of belimumab intravenously after the Food and Drug Administration (FDA)
approval date (March 2011) and before April 2013 were included in this analysis.
Demographic characteristics and SLE treatment of the 68 patients are presented in
Table 1. Data on PGA, SS score, serologic parameters, and prednisone dose were
collected and compared between baseline, 6, and 12 months follow-up. The 68
belimumab-treated patients had a mean baseline PGA of 1.35 and SS score of 4.40;
30 of 68 (48.4%) had positive dsDNA, 15 (22%) low complements, and 55 (82%)
were taking an average dose of 17.8 mg prednisone/d at baseline. The dominant clinical
514 Askanase et al
manifestations were arthritis (52%), mucocutaneous disease (19%), and serositis (8%)
(see Table 2). At 6 months, 58 patients continued belimumab; their mean PGA was
0.91 and SS score 3.09. Twenty-two (53.7%) had a positive dsDNA, 49 (90.7%) had
low complements, and 45 (77.6%) received 14.4 mg of prednisone on average per
day. Of a total of 44 patients who remained on belimumab at 1-year follow-up, 13
(50.0%) had a positive dsDNA, 34 (94.4%) had low complements, and 33 (75%)
received prednisone at an average dose of 16.0 mg/d. The mean PGA score was
0.78, and SS score was 2.30 at 12 months. The reasons for belimumab discontinuation
in the remaining 18 patients included AEs/intolerability (4), lack of efficacy (3), no longer
need it (3), patient preference (3), and insurance reasons (1). This study concluded that
patients who received belimumab plus SOC had statistically significant improved dis-
ease activity after 6 months and 1 year, but no CS-sparing effect of the drug was noted.1
DISCUSSION
Belimumab is the first FDA-approved drug for the treatment of lupus in decades and
marks a breakthrough in drug development in lupus. This article discusses 3 post-
marketing experiences that examined the clinical use of belimumab in the treatment
of SLE patients outside of clinical trials in real-world practices.
In terms of the main clinical manifestations driving treatment, arthritis was the most
common reason for initiating belimumab treatment followed by mucocutaneous dis-
ease and serositis in all 3 studies. Interestingly, another common use of belimumab
was for CS sparing in patients who had received CSs for long periods of time and
had been unable to tolerate dose reduction. Beyond the small amount of data from
patients included in the clinical trials, some patients of the studies reviewed here
received belimumab for stable nephritis and CNS lupus. Results from the limited num-
ber of these patients treated with belimumab are encouraging. The data from the
ongoing severe, active nephritis belimumab clinical trial are eagerly awaited and
may define the role of belimumab in the treatment of lupus nephritis.
Some of the difficulties in managing SLE patients in everyday practice are related to
the measures of efficacy in lupus. SRI is a stringent outcome measure, defined as a
minimum 4 points reduction in SS score, either no new BILAG A or 2 new BILAG
Bs, and a maximum 0.3 point increase in PGA score from baseline. The labor-
intensive nature of the SS and BILAG and the high standard for improvement (to re-
cord improvement in the SS, the clinical manifestation needs to be resolved, which
is an unusual situation in the care of SLE patients) make SRI impractical for routine
clinical use. Physician’s impression of improvement, on the other hand, is easier to
apply in clinical settings because physicians routinely make this assessment in all pa-
tient encounters. Askanase and colleagues and Collins and colleagues used a greater
than or equal to 50% improvement in physician’s impression as the primary outcome
measure of clinical responses. Although this measure has not been formally validated,
data from other studies confirmed that the 50% cut-off is appropriate for capturing the
improvement and efficacy in the treatment of lupus patients.26 Given that physician’s
impression is an investigator-driven measure, problems with subjectivity and lack of
validation are limitations that could potentially confound the findings; some objective
outcome measures were included to reduce such effects.
Responses continued to increase across the 3 studies: Askanase and colleagues
showed 47.8% responders at 3 months and 58.2% responders at 6 months; Yazdany
and colleagues showed that the SS scores decreased from 4.40 at baseline to 3.09 at
6 months and to 2.30 at 12 months. Collins and colleagues showed 47.1% responders
at 6 months and an additional 30.2% between 6 and 12 months; this suggests that the
clinical benefits of belimumab in treating SLE can be observed as early as 3 months

and continue to reduce disease activity throughout the 12-month period. However,
there are several limitations regarding the studies. In Collins and colleagues, the physi-
cian impression of change measured improvement between the beginning and the
end of each individual 6-month study period. It was difficult for physicians to clearly
remember and track the health status of patients at a given time point when patients
were followed across long periods of time. In addition, the measured efficacy of beli-
mumab may have been confounded by the progressive reduction and discontinuation
of CS at 12 months (35%), and by missing data, because not all patient records had
been completed at the time of analysis. The lack of a control group is a limitation of all
these studies.
These 3 studies included patients from diverse racial/ethnic groups, adding to our
understanding of efficacy and safety in these populations and reassuring for the use
of belimumab across all ethnic and racial groups without a decrease in efficacy. In
fact, data from Askanase and colleagues2 suggest a possibly increased benefit in
African Americans. Further data from racial/ethnic minorities are needed to under-
stand whether response is heterogenous across different populations.
Although the sample size is relatively small, these three observational studies
demonstrated that belimumab was generally well tolerated and was safe to incorpo-
rate into standard SLE therapy. No new safety signals were noted with regards to in-
fections, malignancies, depression or deaths. Continued monitoring of long-term
safety of belimumab is further emphasized by the recent report of a case of progres-
sive multifocal leukoencephalopathy in a patient treated with belimumab.27
Overall, these 3 post-marketing experiences support the use of belimumab plus
standard care in SLE patients. Future prospectively designed studies with larger sam-
ple size and longer study duration would allow for a better understanding of the exact
place of belimumab in the SLE therapeutic armamentarium and the long-term effects
of belimumab.
SUMMARY AND FUTURE DIRECTIONS
Data from post-marketing experiences support the safe use of belimumab in addition
to standard SLE therapies in the care of lupus patients. The results of the GSK ran-
domized controlled trials and observational studies will further define the role of beli-
mumab in the SLE treatment algorithm as well as the long-term effects of belimumab.
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20. Jacobi AM, Huang W, Wang T, et al. Effect of long-term belimumab treatment on
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R e c e n t C l i n i c a l Tri a l s i n
Lupus Nephritis
Michael M. Ward, MD
KEYWORDS
Lupus nephritis Randomized controlled trial Cyclophosphamide
Mycophenolate mofetil Azathioprine Cyclosporine Rituximab
KEY POINTS
Low-dose, short-course intravenous cyclophosphamide and mycophenolate mofetil have
efficacy similar to that of standard high-dose intravenous cyclophosphamide for induction
treatment of proliferative lupus nephritis, but these findings may depend on the ethnicity of
the patients studied.
Mycophenolate mofetil is likely more effective than azathioprine as maintenance treat-
ment of proliferative lupus nephritis.
Alternatives to high-dose intravenous cyclophosphamide have a lower risk of ovarian fail-
ure, but risks of other toxicities are not different.
Lack of recent improvement in long-term renal outcomes suggests that new treatment
approaches are needed.
INTRODUCTION
Lupus nephritis (LN) is an autoimmune-mediated glomerulonephritis and tubulointer-

stitial disease that is among the most common and serious manifestations of systemic
lupus erythematosus (SLE). LN develops in 30% to 60% of patients with SLE, most
often occurring early in the course of SLE.1–3 Common accompaniments include ane-
mia, hypertension, hypocomplementemia, and autoantibodies to double-stranded
DNA and the extractable nuclear antigens ribonucleoprotein and Sm.3–5 Rarely, LN
may be the presenting manifestation of SLE in an otherwise asymptomatic patient.
Persons of black African or Hispanic ancestry are 2 to 3 times more likely to develop
LN, and tend to have more severe disease, than white counterparts.3,6,7 Although im-
provements in treatment have transformed severe LN from a near universally fatal
Conflicts of Interest: None.

This work was supported by the Intramural Research Program, National Institute of Arthritis
and Musculoskeletal and Skin Diseases, National Institutes of Health.
Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Dis-
eases, National Institutes of Health, Building 10CRC, Room 4-1339, 10 Center Drive, Bethesda,
MD 20892, USA
E-mail address: wardm1@mail.nih.gov

0889-857X/14/$ – see front matter Published by Elsevier Inc.
520 Ward
condition to a manageable chronic disease, patients with LN are at more than twice
the risk of death than patients without LN, and those with chronic kidney disease
have more than 3 times the risk of death.8,9 Both the high prevalence of LN and the
intensity of clinical care required by patients with LN make it the most costly manifes-
tation of SLE.10
Course of Lupus Nephritis

LN is largely an asymptomatic condition, and requires active screening to be detected.
Clinical and laboratory features reflect the type of renal histologic lesions present in a
given patient. Proteinuria, microscopic hematuria, urinary casts, and hypertension (oc-
casionally severe) are common in patients with proliferative LN, and renal insufficiency
may develop. Nephrotic syndrome with peripheral edema, serous effusions, wasting,
and hypercoagulability can occur in patients with membranous or proliferative LN. LN
can present with acute renal failure, or can be rapidly progressive as a result of severe
glomerular inflammation, cellular crescents, and fibrinoid necrosis, but these presen-
tations are rare.11 In most patients LN is a subacute or chronic condition, with
treatment-induced remissions and spontaneous relapses being fairly common.
Prognosis
Prognosis of LN is closely related to the renal histologic class, and the degree of active
inflammation and chronic damage incurred.12–14 Patients with mesangial LN have only
mild laboratory abnormalities and very low risk of chronic kidney disease. Patients
with membranous LN often have morbidity related to nephrosis but more than 90%
achieve remission, and, excluding transitions to a proliferative subtype, fewer than
10% of patients progress to end-stage renal disease after 15 years.15,16 In patients
with proliferative LN the prognosis is poorer in those with diffuse than with focal
glomerular involvement, and in those with crescents and extensive chronic damage.14
End-stage renal disease develops in 25% to 40% of patients with proliferative LN after
15 years, predominantly among those with diffuse involvement.5,17,18 Advanced scle-
rosing glomerulonephritis represents an end-stage inactive lesion with more than 90%
of glomeruli showing global sclerosis, with a high risk of end-stage renal disease.
Additional poor prognostic factors include delayed initiation of immunosuppressive
treatment, incomplete response to induction therapy, occurrence of nephritic re-
lapses, and poor control of hypertension.19
Goals of Treatment
The goals of treatment of LN are to prevent end-stage renal disease and to decrease
the risk of chronic kidney disease and its atherosclerotic and metabolic conse-
quences. Treatment can also facilitate control of blood pressure and help avoid the
vascular complications of hypertension. In addition, treatment of nephrotic syndrome
can lessen the morbidity associated with fluid overload, hypoalbuminemia, and the
risk of thrombosis.
It is important to recognize that, apart from proteinuria, these goals are not typically
measured as outcomes in controlled clinical trials in LN. Chronic kidney disease and
end-stage renal disease are often late manifestations, and impractical to measure in
short-term clinical trials. Even 5 years of follow-up may not be sufficient to see differ-
ences in risks of these outcomes. The large functional reserve of kidneys makes mea-
sures of renal function insensitive to even moderate degrees of dysfunction. Doubling of
the serum creatinine level has questionable validity for predicting long-term renal out-
comes in patients with good renal function at baseline.20 Recent clinical trials have used
improvement or normalization of proteinuria, improvement in urine sediment, and
stabilization or improvement in serum creatinine levels as end points. Although the

rationale that reductions in signs of active inflammation should translate into lower risks
of kidney damage and dysfunction in the future is sound, the definitions of response in
clinical trials have not been validated as good surrogate markers of late renal outcomes.
Traditional Treatment Approach

A shift from using glucocorticoids alone to using cytotoxic drugs together with gluco-
corticoids to treat serious LN occurred in the 1970s and 1980s with evidence from clin-
ical trials of improved renal outcomes from combination therapy.21 A central role for
cyclophosphamide (CYC) was solidified based on trials conducted at the National In-
stitutes of Health (NIH), which showed numerically better outcomes after 10 years
among patients with active (mostly proliferative) LN treated with intravenous CYC in
comparisons with those treated with azathioprine or prednisone alone.22 Trials showing
that prolonged treatment with CYC resulted in fewer nephritic flares and lower risks of
end-stage renal disease ushered in the notion of induction and maintenance phases of
treatment of LN, and established the “NIH regimen” of monthly intravenous CYC for
6 months followed by quarterly infusions for 24 additional months as acceptable for
the treatment of severe LN.23,24 However, treatment-related complications including
infection, ovarian failure, hemorrhagic cystitis, bladder cancer, and treatment-related
mortality emerged as concerns.25
The need for treatments with less toxicity and equal or better efficacy has motivated
studies of new medications, and new methods of administering CYC. This article re-
views recent clinical trials of new medications or treatment strategies for LN. The re-
view is limited to medications that are currently available in the clinic because these
can be used by clinicians today, and is further limited to published full-length studies
of adults with LN.
TRIALS OF ALTERNATIVE DOSING OF CYCLOPHOSPHAMIDE

Euro-Lupus Nephritis Trial
This randomized controlled trial compared a short-course regimen of low-dose intra-
venous CYC with a longer regimen of higher-dose intravenous CYC as induction treat-
ment of active proliferative LN.26 The experimental group was given 500 mg of
intravenous CYC every 2 weeks for 6 doses, whereas the control group was treated
with 0.5 g/m2 body surface area of intravenous CYC monthly for 6 doses, followed
by 2 additional doses at 9 months and 12 months. In the control group the dose of
CYC was sequentially increased, based on nadir peripheral blood leukocyte counts,
to a maximum of 1500 mg. Both groups received pulse methylprednisolone at the start
of treatment, followed by tapering doses of prednisone, and received azathioprine
2 mg/kg daily for maintenance treatment at the end of the CYC course.
The primary end point was treatment failure, defined as either persistent renal insuf-
ficiency or nephrotic syndrome, glucocorticoid-resistant flare, or doubling of the
serum creatinine level. End points were assessed in a time-to-event analysis with a
median follow-up of 41 months. The occurrence of the primary end point did not differ
between treatment groups (Table 1). The probability of renal remission (71% vs 54%)
and renal flare (27% vs 29%) over time also did not differ between the low-dose and
high-dose groups. Two patients in the low-dose group died and 1 progressed to end-
stage renal disease while 2 patients in the high-dose group progressed to end-stage
renal disease. Severe infections were more common in the high-dose group while the
frequencies of nonserious infections, leukopenia, and ovarian failure were similar in the
2 treatment groups.
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Table 1
Controlled trials of alternative dosing of cyclophosphamide (CYC) as induction treatment
Intervention N Primary End Outcomes (%)

Study,Ref. Year Design Experimental Control Experimental Control Pointa Experimental Control
Euro-Lupus,26 Superiority CYC 0.5 g every CYC 0.5 g/m2 44 46 Treatment 16 20
2002 2 wk 6 monthly 6, then failure
quarterly 2
Petri et al,28 Superiority CYC 50 mg/kg CYC 0.75 g/m2 10 12 Complete 20 64
2010 daily 4 monthly 6, then response
quarterly for 2 y
Sabry et al,29 Superiority CYC 0.5 g every CYC 0.5 g/m2 20 26 Treatment 5 3.4
2009 2 wk 6 monthly 6, then failure
quarterly 2
Mitwalli et al,30 Superiority CYC 5 mg/kg CYC 10 mg/kg 44 73 Patient 100 at 6 mo, no 100 at 6 mo, no
2011 monthly 6, then monthly 6, then and renal results for long results for long
every 2 mo 18 every 2 mo 6 survival term term
a
Defined in text.
The investigators concluded that the low-dose CYC regimen was comparable in
efficacy with the higher-dose regimen in patients with proliferative LN, and that a
high-dose regimen was not required as treatment for all patients with proliferative
LN. However, the investigators noted that although most patients had diffuse prolifer-
ative LN, the majority did not have severe disease, with 22% having an elevated serum
creatinine and 28% with nephrotic syndrome at study entry. The trial included few
ethnic minorities. The results may not be generalizable to patients with more severe
LN. Although the low-dose regimen was anticipated to have less toxicity, and was
associated with fewer serious infections, other adverse events were similar between
the treatment groups.
Several points are worth noting. Although presented as a superiority trial, an a priori
power calculation was not apparent, and consequently the interpretation of statistical
differences is difficult. A larger sample would be needed to convincingly demonstrate
noninferiority between the treatments. The primary end point consisted of an absence
of worsening for most patients, rather than demonstration of improvement. Therefore
the possibility of persistent LN activity among “responders” also raises questions
about how the results should be interpreted. Renal outcomes in both groups were
excellent at 10 years, suggesting that residual activity did not affect long-term out-
comes, although most patients still required immunosuppressive treatment.27 The
high-dose CYC regimen was shorter than the typical NIH regimen, which somewhat
complicates comparisons among studies. However, the results of this trial suggest
that the intensity of immunosuppression can be tailored to the severity of disease
among patients with proliferative LN.
Myeloablative Regimen
This randomized trial compared the efficacy of a myeloablative regimen of intravenous
CYC with that of monthly intravenous CYC followed by quarterly infusions for 3 years,
following the NIH regimen.28 The rationale for testing myeloablative treatment was to
attempt to eliminate autoreactive lymphocytes and reset the immune system. Patients
with treatment-refractory SLE were eligible, and although the study was not limited to
patients with LN, data on those with LN were reported separately. Complete response
required a normal serum creatinine, normal creatinine clearance, normal urinary sedi-
ment, and proteinuria less than 500 mg/d. Complete responses were rare at 6 months,
but were more common among those treated with the NIH regimen than with the mye-
loablative regimen at 30 months (see Table 1).
Additional Trials
Sabry and colleagues29 replicated the Euro-Lupus Nephritis Trial in a 12-month ran-
domized trial in 46 patients with proliferative LN. No differences in outcomes were
observed, but the power of the study was limited. Mitwalli and colleagues30 found
no difference in patient and renal survival between patients randomized to short-
term high-dose intravenous CYC and a longer course of lower-dose CYC.
TRIALS OF AZATHIOPRINE, CYCLOSPORINE, OR TACROLIMUS AS ALTERNATIVES TO

CYCLOPHOSPHAMIDE AS INDUCTION TREATMENT
Dutch Working Party Trial
This randomized trial compared treatment with azathioprine, 2 mg/kg daily along with
3 courses of pulse methylprednisolone, with the NIH regimen of intravenous CYC in
patients with proliferative LN.31 At entry, 56% of patients had renal impairment and
53% had nephrotic-range proteinuria. Over a median follow-up of 5.7 years, 4 times
as many patients in the azathioprine group as in the CYC group met the primary
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end point of doubling of serum creatinine (Table 2). Although the likelihood of com-
plete remission was similar in the 2 treatment groups over the first 2 years of the study,
relapses were higher in the azathioprine group (7.1 per 100 patient-years vs 1.1 per
100 patient-years). Infections, particularly herpes zoster, were more common in the
azathioprine group. On extended follow-up to a median of 9.6 years, the azathioprine
group had numerically higher frequency of doubling of serum creatinine (16% vs 8%),
mortality (16% vs 10%), and renal relapses (38% vs 10%).32 Although the reports
emphasized the lack of significant differences in end points other than relapses, the
power of the study to detect differences in other outcomes was limited, and the weight
of evidence suggests greater efficacy for intravenous CYC than for azathioprine.
Trials of Calcineurin Inhibitors

Chen and colleagues33 compared outcomes at 6 months between patients with active
LN (89% proliferative; 11% membranous) treated with either tacrolimus (0.05 mg/kg
daily, titrated to serum trough levels of 5–10 ng/mL) or intravenous CYC by the NIH
regimen in a randomized noninferiority trial (see Table 2). At entry, 10% of patients
had elevated serum creatinine and 43% had nephrotic-range proteinuria. Complete
remission at 6 months was seen in 52% of tacrolimus-treated patients and 38% of
CYC-treated patients, with most failures attributable to persistent proteinuria. The
study enrolled only one-half of the projected sample size needed to adequately test
noninferiority. In a smaller trial of similar design, Li and colleagues34 reported complete
or partial remission in 75% of tacrolimus-treated patients and 60% of CYC-treated pa-
tients at 6 months. Responses after 9 months of treatment were also similar in a small
trial that compared cyclosporine with intravenous CYC.35 Notable in these studies is
the rapid improvement in proteinuria and generally good responses regardless of
treatment arm, but their small sizes limit the strength of any comparisons.
TRIALS OF MYCOPHENOLATE MOFETIL AS INDUCTION TREATMENT
Seven trials have compared mycophenolate mofetil (MMF) with CYC as induction
treatment for LN (Table 3).34,36–41 Five trials included fewer than 50 patients, and 4
of these 5 trials reported similar treatment effects at 6 months. Bao and colleagues39
studied combined treated with MMF and tacrolimus versus intravenous CYC in pa-
tients with LN of mixed class V and IV, and found that combined treatment led to
more complete remissions. The 2 largest studies are reviewed in more detail.
Noninferiority Study
Ginzler and colleagues40 tested the noninferiority of MMF to intravenous CYC in a 6-
month study of induction treatment in patients with active proliferative (81%) or mem-
branous (19%) LN. Patients were randomized to treatment with either open-label MMF
at 1000 to 3000 mg daily or intravenous CYC by the NIH regimen. The primary end
point was complete remission at 6 months, defined as normalization of the serum
creatinine level, proteinuria, and urinary sediment. An early response to treatment at
12 weeks was required for patients to continue treatment through 24 weeks, and those
without an early response were offered the option to cross over to the alternative
treatment.
Seventy-six percent of patients were black or Hispanic. Patients had active nephritis
with a mean serum creatinine of 1.07 mg/dL, and 44% had nephrotic-range protein-
uria at study entry. Mean doses of MMF were greater than 2500 mg daily, and only
62% of those in the CYC group completed all infusions. Early responses were seen
in 79% of the MMF group and 61% of the CYC group, and these patients completed
Table 2
Comparative controlled trials of azathioprine, cyclosporine, or tacrolimus as induction treatment
Intervention N Outcomes (%)

Study,Ref. Year Design Experimental Control Experimental Control Primary End Pointa Experimental Control
Dutch Working Superiority Azathioprine 2 mg/kg CYC 0.75 g/m2 monthly 37 50 Doubling of serum 16 4
Party,31 2006 daily and pulse 6, then quarterly creatinine
methylprednisolone 9 for 21 mo
Chen et al,33 Noninferiority Tacrolimus 0.05 mg/kg CYC 0.75 g/m2 42 39 Complete remission 52 38
2011 daily, titrated to trough monthly 6
levels
Recent Clinical Trials in Lupus Nephritis

Li et al,34 2012 Superiority Tacrolimus 0.08–0.1 mg/kg CYC 0.5–0.75 g/m2 20 20 Complete or partial 75 60
daily, titrated to trough monthly 6 remission
levels
Cyclofa-Lune,35 Superiority 4–5 mg/kg daily 9 mo CYC 10 mg/kg 8 19 21 Complete remission 26 24
2010 over 9 mo
a
Defined in text.
525
526
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Table 3
Trials of mycophenolate mofetil (MMF) as induction treatment
Intervention N Outcomes (%)

Study,Ref. Year Design Experimental Control Experimental Control Primary End Pointa Experimental Control
Li et al,34 2012 Superiority MMF 1500–2000 mg daily CYC 0.5–0.75 g/m2 20 20 Complete or partial 75 60
monthly 6 remission
Chan et al,36 2000 Superiority MMF 2000 mg daily Oral CYC 2.5 mg/kg daily 21 21 Complete remission 81 76
6 mo, then azathioprine
1.5 mg/kg daily
El-Shafey et al,37 Noninferiority MMF 2000 mg daily CYC 0.5–1.0 g/m2 24 23 Complete or partial 58 52
2010 monthly 6 remission
Ong et al,38 2005 Superiority MMF 2000 mg daily CYC 0.75–1.0 g/m2 19 25 Complete or partial 58 52
monthly 6 remission
Bao et al,39 2008 Superiority MMF 2000 mg daily and CYC 0.75 g/m2 monthly 9 20 20 Complete remission 65 15
tacrolimus 4 mg daily
Noninferiority Noninferiority MMF 1000–3000 mg daily CYC 0.5–1.0 g/m2 71 69 Complete remission 22.5 5.8
study,40 2005 monthly 6
ALMS,41 2009 Superiority MMF 1000–3000 mg daily CYC 0.5–1.0 g/m2 185 185 Renal response 56.2 53
monthly 6
a
Defined in text.
6 months of the assigned treatment. More patients in the CYC group withdrew from
the trial before week 12 (10 vs 6 in the 2 treatment groups). Eight patients crossed
over to the alternative treatment.
In the intent-to-treat analysis, more patients in the MMF group than in the CYC
group had complete remission at 6 months (22.5% vs 5.8%), a difference that
exceeded the threshold for noninferiority. Results were similar among patients who
completed their assigned treatment. The frequency of partial remission was similar be-
tween the groups (29.6% vs 24.6%), as were improvements in serum creatinine levels,
proteinuria, and urinary sediment. Severe infections were more common in the CYC
group, and there were 2 deaths in this group. Diarrhea was more common in the
MMF group. Although the study found more frequent complete remissions in
the MMF-treated patients, this finding turned on the rapidity of response, owing to
the design of early escape at 12 weeks. The high number of withdrawals, particularly
in the CYC group, complicates the interpretation.
ALMS
The Aspreva Lupus Management Study (ALMS) was designed to test whether MMF
was superior to intravenous CYC as induction treatment of active LN.41 This large
multinational study enrolled patients with active, or active and chronic, proliferative,
or membranous LN. Those patients with class III or class V LN were required to
have proteinuria of 2 g/d or more. Patients were randomized to open-label MMF
with a target dose of 3000 mg daily, or intravenous CYC by the NIH protocol. Patients
who worsened over the first 12 weeks of the trial were withdrawn. The primary end
point was renal response, defined as improvement in proteinuria and stabilization or
improvement in the serum creatinine level. The study was planned to enroll enough
patients so that a 15% difference in renal response between groups would be
detected as statistically significant, should a difference of this magnitude be observed.
Mean serum creatinine level at entry was 0.8 mg/dL, and the mean urine protein/
creatinine ratio was 4.1. Sixteen percent of patients had membranous LN. The treat-
ment groups were well balanced. Eighty-three percent of the 307 patients completed
the 6-month study. Most patients in the MMF group took more than 2500 mg daily,
and the median CYC dose was 0.75 mg/m2, with a mean number of infusions per pa-
tient of 5.6. In contrast to the MMF noninferiority study, withdrawals were not more
frequent in the CYC group.
Renal response was seen in 56.2% of patients in the MMF group and 53% of pa-
tients in the CYC group in the intent-to-treat analysis. Renal responses were also
similar when those who completed the trial were analyzed separately (63.7% vs
57.1%), as were frequencies of normalization of serum creatinine and proteinuria.
Eight percent of patients in each group achieved complete remission at 6 months.
Adverse events, including infections, were similar between groups, but severe gastro-
intestinal events were somewhat more frequent in the MMF group. There were 9
deaths in the MMF group and 5 deaths in the intravenous CYC group.
The investigators concluded that the efficacy and tolerability of MMF and intrave-
nous CYC as induction treatment over 6 months were similar. Given the low propor-
tion of complete remissions, they speculated that longer induction periods may be
needed to differentiate between treatments. In an interesting subanalysis, renal re-
sponses were substantially more common with MMF treatment than with CYC treat-
ment among the subgroup of black and Latin patients, whereas little difference was
present among whites or Asians. This finding may explain the results favoring MMF
in the study by Ginzler and colleagues,40 which largely included black and Hispanic
patients.
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TRIALS OF ALTERNATIVES TO PROLONGED TREATMENT WITH CYCLOPHOSPHAMIDE

AS MAINTENANCE TREATMENTS
Miami Study
Contreras and colleagues42 tested the efficacy of maintenance treatment with either
azathioprine or MMF with that of intravenous CYC given every 3 months in a random-
ized trial of patients with proliferative LN who had completed a maximum of 7 monthly
infusions with intravenous CYC as induction treatment (Table 4). The azathioprine
group received 1 to 3 mg/kg daily (mean 1 mg/kg), the MMF group received 500 to
3000 mg daily (mean 1500 mg), and the CYC group received 0.5 to 1.0 g/m2 body sur-
face area (mean 0.55 g/m2). Patients also were treated with prednisone up to 0.5 mg/kg
daily. Maintenance treatments were continued long term, with median durations of
30 months, 29 months, and 25 months in the azathioprine, MMF, and CYC groups,
respectively.
Patients were predominantly black (45%) or Hispanic (49%) and had severe prolif-
erative LN, with mean serum creatinine at entry of 1.6 mg/dL, hypertension (97%), and
nephrotic syndrome (64%). Most patients responded to induction treatment, with no
imbalances among maintenance treatment groups.
The primary end points were patient survival and renal survival, defined as either
sustained doubling of serum creatinine or end-stage renal disease. At 60 months, pa-
tient survival was significantly lower in the CYC group (57%) than in the azathioprine
group (100%) and the MMF group (94%). Chronic renal disease developed in 15%,
5%, and 5% in the CYC, azathioprine, and MMF groups, respectively, with renal sur-
vival of 74%, 80%, and 95%. Relapse-free survival was higher in the MMF group. In-
fections, hospital days, and amenorrhea were more common in the CYC group.
The investigators concluded that maintenance treatment with MMF or azathio-
prine following induction treatment with intravenous CYC was superior in both out-
comes and tolerability to continued intravenous CYC as maintenance treatment.
This study highlighted the potential for alternative treatments to avoid toxicities
associated with prolonged CYC treatment, and raised the notion that patient
ethnicity may influence responses to different treatments. However, the mechanisms
underlying the poorer response to CYC than to azathioprine or MMF as maintenance
treatment is unclear, given that patients had responded to induction treatment
with CYC.
ALMS
Maintenance treatment options were compared in a follow-on study in patients who
had acceptable clinical responses to either MMF or intravenous CYC in the ALMS in-
duction study. After the 6-month induction trial, this trial rerandomized patients to
treatment with either MMF 2000 mg daily or azathioprine 2 mg/kg daily for
36 months.43 Randomization was stratified by the type of induction treatment patients
had received (MMF or CYC), ethnicity, and renal histologic class, to produce groups
similar in these characteristics. Sixty-three percent of patients treated with MMF
and 48% of patients treated with azathioprine completed 36 months of observation,
with most withdrawals attributable to adverse events. The primary end point was treat-
ment failure, defined as any of the following events: death, end-stage renal disease,
sustained doubling of the serum creatinine level, renal flare, or need for additional
immunosuppression to treat active LN.
MMF was superior to azathioprine in the proportion of patients meeting the primary
end point, with fewer patients having treatment failure (16% vs 32%) and a lower risk
of treatment failure in a time-to-event analysis (hazard ratio 5 0.44). Renal flares and
Table 4
Comparative trials of alternative maintenance treatments
Intervention N Primary End Outcomes (%)

Study,Ref. Year Design Experimental Control Experimental Control Pointa Experimental Control
Miami,42 2004 Superiority Azathioprine 1–3 mg/kg CYC 0.5–1.0 g/m2 Azathioprine 5 19; 20 Patient and Azathioprine: Patient 57;
daily or MMF 500– quarterly MMF 5 20 renal patient 100; renal 74
3000 mg daily survival renal 80
MMF: patient 94;
renal 95
ALMS,43 2011 Superiority MMF 2000 mg daily Azathioprine 2 mg/kg 116 111 Treatment 16 32
Recent Clinical Trials in Lupus Nephritis

daily failure
MAINTAIN,44 Superiority MMF 2000 mg daily Azathioprine 2 mg/kg 53 52 Renal flare 19 25
2010 daily
Moroni et al,45 Superiority Cyclosporine 4 mg/kg Azathioprine 2 mg/kg 36 33 Renal flare 10.6 per 100 13.4 per 100
2006 daily daily patient-years patient-years
a
Defined in text.
529
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the need for additional immunosuppression were also less common in the MMF
group. End-stage renal disease occurred in 2.7% of azathioprine-treated patients
but in no MMF-treated patients. Adverse events were similar in the 2 groups, with in-
fections in 78% and serious infections in 10% to 12% of patients. The strengths of this
study were its large size and blinding using a double-dummy method, wherein all pa-
tients took both active and placebo pills for the alternative medications. Consistency
of results among many different end points also strengthens the evidence in favor of
MMF. However, it is important to recognize that most patients treated with azathio-
prine also did well.
MAINTAIN
This study (Mycophenolate Mofetil versus Azathioprine for Maintenance Therapy of
Lupus Nephritis) tested maintenance treatment with either azathioprine or MMF in pa-
tients with proliferative LN after induction treatment with intravenous CYC using the
Euro-Lupus protocol.44 Patients entered with active LN (mean serum creatinine
1 mg/dL; 10% with renal insufficiency; 39% with nephrotic-range proteinuria) and all
were treated with pulse methylprednisolone and 6 infusions of CYC before being ran-
domized to either azathioprine 2 mg/kg daily or MMF 2000 mg daily, regardless of their
response to CYC. The primary end point was renal flare, defined as either develop-
ment of nephrotic syndrome, an increase in serum creatinine, or an increase in protein-
uria accompanied by hematuria and depression of C3 levels.
Seventy-four percent of patients were taking the assigned medication at 3 years,
with the mean azathioprine dose ranging from 100 to 125 mg daily, and the mean
MMF dose ranging from 1600 to 2000 mg daily. During follow-up, renal flares were
observed in 25% of patients treated with azathioprine and 19% of those treated
with MMF. Times to severe flare and renal remission were similar between groups.
In a subanalysis of patients who had a primary response to treatment, 14% of patients
in both treatment groups developed a subsequent renal flare. One patient in each
group developed end-stage renal disease, and 2 patients in the MMF group died.
Cytopenias were more common in the azathioprine group, but infections were equally
frequent.
The study was designed to test the superiority of MMF relative to azathioprine, and
the investigators concluded that there was insufficient evidence to support superiority.
In contrast to the ALMS trial, treatments were open-label rather than blinded, and pa-
tients were not enrolled based on their response to induction treatment. The primary
outcome was also more focused in MAINTAIN, which may have lessened the oppor-
tunity to detect differences between treatment groups, as would the smaller sample.
The ethnic composition of the study group might have also affected assessment of the
relative efficacy of these 2 medications if MMF has particular benefit in ethnic
minorities.
Cyclosporine Versus Azathioprine

Moroni and colleagues45 compared cyclosporine 4 mg/kg daily with azathioprine
2 mg/kg daily as maintenance treatment for patients with proliferative LN after induc-
tion treatment with pulse methylprednisolone and oral CYC 1 to 2 mg/kg daily for
3 months. Seven renal flares, either proteinuric or nephritic (with an increase in serum
creatinine level), occurred in the cyclosporine group, for a rate of 10.6 flares per 100
patient-years of treatment, whereas 8 renal flares occurred in the azathioprine group,
for a rate of 13.4 flares per 100 patient-years. Improvements in serum creatinine levels
and proteinuria were similar in the 2 groups, but comparisons were hampered by the
small sample.
TRIAL OF RITUXIMAB
LUNAR
The Lupus Nephritis Assessment with Rituximab (LUNAR) study was a randomized,
placebo-controlled trial designed to test whether treatment with rituximab could boost
complete renal responses among patients with active LN when added to other immu-
nosuppressive treatments.46 This study was motivated by the suboptimal rates of
complete responses to induction treatment seen with MMF or intravenous CYC in pa-
tients with active proliferative LN. In this trial all patients were started on induction
treatment with MMF 3000 mg daily and pulse methylprednisolone. In addition, blinded
treatment with rituximab (1 g) or placebo was given on days 1, 15, 168, and 182 of
treatment, with 72 patients in each group. The primary outcome was complete renal
response, defined as normalization or stabilization of the serum creatinine level, and
normalization of the urinary sediment and proteinuria. Rituximab was effective in
B-cell depletion. At 52 weeks, 26.4% of patients in the rituximab group had complete
renal response, compared with 30.6% in the placebo group. Partial responses were
numerically higher in the rituximab group, and serologic parameters improved more
in this group, but other renal responses did not differ. Two deaths occurred in the rit-
uximab group while the risks of other adverse events, including serious infections,
were not different between treatment groups.
Despite encouraging results from many observational studies and uncontrolled tri-
als,47 this study demonstrated lack of benefit from rituximab when added to a regimen
of MMF and corticosteroids for induction treatment. The study was not designed to
test whether rituximab could be an acceptable replacement for other induction med-
ications, nor if the use of rituximab would permit more rapid tapering of corticosteroids
or reduced doses of MMF without worsening control of LN.48 Combining rituximab
with MMF did not result in additional safety concerns.
TRIALS IN MEMBRANOUS LUPUS NEPHRITIS
Membranous LN has commonly been treated with alternate-day corticosteroids,

although studies have also investigated the effectiveness of cyclosporine, tacrolimus,
MMF, and CYC. Austin and colleagues49 performed an open-label randomized trial
comparing cyclosporine 200 mg/m2 daily and high-dose alternate-day prednisone,
intravenous CYC 0.5 to 1.0 g/m2 every other month for 6 infusions and high-dose alter-
nate-day prednisone, and high-dose alternate-day prednisone alone in 42 patients
with membranous LN and proteinuria of at least 2 g daily (median 5.4 g daily). At
12 months, remission was present in 83% of patients treated with cyclosporine,
60% treated with CYC, and 27% treated with prednisone alone. Patients in the cyclo-
sporine group responded more rapidly, but were also more likely than those treated
with CYC to relapse on discontinuation of treatment. However, either medication pro-
vided better short-term control of proteinuria than corticosteroids alone.
Radhakrishnan and colleagues50 performed a subanalysis of patients with membra-
nous LN who were enrolled in 2 trials of induction treatment that compared intravenous
CYC and MMF. Among 24 patients in the noninferiority study by Ginzler and colleagues40
and 60 patients in the ALMS, improvements in proteinuria and serum creatinine were
similar between those treated with intravenous CYC or MMF in a completers analysis.
SYNTHESIS OF THE EVIDENCE

Cochrane Review
In a review of 50 randomized controlled trials, most of which investigated induction treat-
ment, Henderson and colleagues25 concluded that MMF was as effective as intravenous
532 Ward
cyclophosphamide for induction treatment while having lower risks of ovarian failure.
Moreover, MMF was more effective than azathioprine as maintenance treatment, but
there were insufficient data on other treatments to provide adequate comparisons.
American College of Rheumatology Treatment Recommendations
Using a systematic literature review and the RAND/UCLA Appropriateness method,
researchers developed a series of recommendations for approaches to the treatment
of patients with LN.51 This panel recommended pulse methylprednisolone and either
MMF or intravenous CYC for induction treatment in patients with proliferative LN, with
varied preferences between treatments based on the ethnicity of the patient. Mainte-
nance treatment was recommended with either MMF or azathioprine, with rituximab or
calcineurin inhibitors as second-line agents. The panel recommended MMF as the
initial treatment for patients with membranous LN with nephrotic-range proteinuria.
Despite these recommendations, there remains substantial controversy among
rheumatologists and nephrologists on the most appropriate first-line therapy for pa-
tients with severe LN.52
SUMMARY
These trials demonstrate the progress has been made in the past 15 years in the treat-
ment of patients with LN but also that current treatment is not curative. Direct compar-
isons among these studies are complicated by the use of different end points. While
consensus is evolving on the most appropriate end points for studies of induction
treatment, more work is needed on linking the outcomes measured in short-term trials
to future end-stage renal disease, comorbidities, and mortality. The length of induction
treatment may need reconsideration to produce more durable responses. Because
most studies focus on short-term responses, it is not clear how the treatment changes
tested in these trials will affect the frequency of important long-term outcomes, partic-
ularly end-stage renal disease. Some evidence suggests that long-term outcomes of
LN have not improved in recent years, raising the question of whether currently avail-
able treatments can provide the results clinicians want and patients need.53–55
The introduction of low-dose regimens, and differences in responses based on pa-
tient ethnicity, suggest that the most important advance may have been a change in
philosophy from use of a uniform protocol to more individualized or tailored treatment.
Further testing of medications for equivalence or superiority will likely not yield impor-
tant advances. At present, the most important clinical question is: between 2 medica-
tions that are similarly effective on the group level, which patients will need the more
toxic or expensive medication, and which patients will do well, now and in the long
term, with the least toxic and least expensive treatment?
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The Kidney Biopsy in Lupus
N e p h r i t i s : Is It Still Relevant?
Brad H. Rovin, MD*, Samir V. Parikh, MD, Anthony Alvarado, MD
KEYWORDS
Lupus nephritis Kidney biopsy Systemic lupus erythematosus
KEY POINTS
The kidney biopsy is the standard of care for diagnosis of lupus nephritis and remains
necessary to ensure accurate diagnosis and guide treatment.
Repeat biopsy should be considered when therapy modifications are necessary, as in
cases with incomplete or no response, or when stopping therapy for those in remission.
There are several promising biomarkers of kidney disorders; however, these markers
needed to be validated in a prospective clinical trial before being applied clinically.
Molecular analysis may provide the information presently lacking from current evaluation
of kidney disorders and may better inform prognosis and treatment considerations.
INTRODUCTION
The percutaneous kidney biopsy was introduced in the 1940s and incorporated into
clinical practice in the 1950s.1,2 This procedure, along with advances in the histopath-
ologic examination of kidney tissue such as immunofluorescence and electron
microscopy, greatly enhanced understanding of the pathogenesis of human glomeru-
lonephritis. Perhaps more than for any of the other glomerular diseases, biopsy find-
ings have been used to classify and subgroup lupus nephritis (LN) in order to inform
treatment decisions and predict prognosis. Several LN classification schemes have
been applied clinically, the most recent being from collaboration between the Interna-
tional Society of Nephrology and the Renal Pathology Society in 2004.3 In an effort to
forecast kidney outcomes, pathologic findings in LN have also been combined into
composite indices of active and chronic disease independent of LN class.4,5
The role of the kidney biopsy in LN has recently been challenged on several fronts:
(1) the widespread clinical practice of using mycophenolate mofetil (MMF) for
Disclosures: None.
Nephrology Division, Department of Internal Medicine, Ohio State University Wexner Medical
Center, 395 West 12th Avenue, Columbus, OH 43210, USA
* Corresponding author. Medical Office Tower, Ground Floor, 395 West 12th Avenue, Colum-
bus, OH 43210.
E-mail address: rovin.1@osu.edu

538 Rovin et al
induction treatment of proliferative and membranous LN has led many clinicians to

question the need for diagnostic biopsies to guide therapy. (2) Diagnostic biopsies
do not predict treatment response or long-term kidney outcomes in LN, and the added
value of serial biopsies remains unclear. (3) Noninvasive biomarkers of renal disorders
are actively being sought to substitute for invasive kidney biopsies. (4) The kidney bi-
opsy is still only analyzed histologically, whereas molecular diagnostics are being
applied to biopsies of other diseases to personalize therapy.
In light of these challenges, this article reexamines the kidney biopsy in LN in order
to assess its ongoing relevance to disease management, and considers how molec-
ular analyses can increase the information derived from the kidney biopsy.
WHEN AND HOW OFTEN DOES A PATIENT WITH LN NEED A KIDNEY BIOPSY?
An evidence-based literature has developed around this question, but to date there is
no consensus answer. Three possible responses are considered here.
1. A kidney biopsy should routinely be obtained to confirm the diagnosis of LN before
treatment is started.
This traditional approach is used when patients with systemic lupus erythematosus
(SLE) develop clinical evidence that is consistent with renal involvement by lupus and
that cannot be explained by other conditions. These clinical findings include hematu-
ria, pyuria, red and white blood cell casts, declining kidney function, and/or protein-
uria.6 Dysmorphic red blood cells, specifically acanthocytes (Fig. 1), indicate
glomerular hematuria and are often seen in the urine sediment of patients with LN
with active nephritis. Red blood cell casts (see Fig. 1) also indicate glomerular hema-
turia, but are found less commonly. Urine white blood cells and white blood cell casts,
in the absence of kidney or urinary tract infection, are consistent with kidney inflamma-
tion caused by LN. A kidney biopsy is generally not indicated for hematuria or pyuria
alone, but patients who develop active urine sediment require close follow-up for signs
of worsening kidney injury such as proteinuria and an increase in serum creatinine.
Besides LN, the differential diagnosis of renal dysfunction in patients with SLE in-
cludes tubular injury caused by systemic infection or nephrotoxins. Patients with lupus
are susceptible to infection because they are routinely immunosuppressed, and often
Fig. 1. Urine findings of glomerular hematuria in LN. (A) Acanthocytes are a type of dysmor-
phic red blood cell that is specific for glomerular hematuria. The arrow indicates a bleb that
distorts the normal biconcave disc appearance of the red blood cell. (B) Red blood cell casts
also indicate glomerular bleeding.
Kidney Biopsy in Lupus Nephritis 539
receive medications that are potentially nephrotoxic. Renal insufficiency caused by LN

is usually accompanied by proteinuria and/or hematuria.
The most common clinical finding that triggers a request for kidney biopsy in pa-
tients with SLE is proteinuria of at least 500 to 1000 mg/d, in the presence or absence
of renal insufficiency or active urine sediment. Although there is no set proteinuria
threshold for biopsy, patients with proteinuria of 500 mg/d or less can have severe
LN.7 In a pilot study of 38 patients with lupus undergoing a kidney biopsy for the first
time, and who had glomerular hematuria with less than 500 mg/d proteinuria, 95% of
the patients had class III, IV, or V LN, and only 5% had class II.8 These data show the
difficulty of estimating kidney involvement in SLE using clinical data without histologic
examination of the kidney.
2. A kidney biopsy is not routinely needed before starting therapy for LN.
This nontraditional approach is mainly a response to the overwhelming acceptance
of MMF as first-line therapy for all of the serious forms of LN (class III, IV, and V),9 theo-
retically eliminating the need to differentiate between classes before starting therapy.
Furthermore, it has been difficult to show that the pathologic findings at diagnostic kid-
ney biopsy prognosticate how the kidney will do in the long term or how it will respond
to therapy in the short term.10,11 However, it has been shown that a kidney biopsy
done after completion of induction therapy does provide prognostic information on
renal outcomes.10,11 It may therefore be advantageous to delay biopsy until induction
treatment is finished.
In contrast, we suggest a diagnostic kidney biopsy before therapy is necessary for
the following practical (1–3) and theoretic reasons (4): (1) patients with SLE may also
develop glomerular diseases that are not the classic immune complex–mediated
glomerulonephritis that is defined as LN. Most commonly these are histologically
similar to minimal change disease or focal segmental glomerulosclerosis, and have
been termed lupus podocytopathies, but other disorders can also be seen.12–15 The
incidence of non–immune-complex glomerulonephritis in patients with SLE is hard to
estimate, but was 5% in a series of more than 200 patients with SLE.13 These glomer-
ulopathies cannot be distinguished from LN clinically; a biopsy diagnosis is required.
Furthermore, the treatment of non–immune-complex nephritis is not necessarily the
same as for LN. For example, the lupus podocytopathies often respond to short
courses of corticosteroids alone, and do not need the addition of a cytotoxic agent.16
(2) Renal thrombotic microangiopathy caused by antiphospholipid syndrome is found
in about 30% of patients with lupus, and can occur alone or with classic immune-
complex LN.17–19 Renal thrombotic microangiopathy cannot be diagnosed without a
biopsy. It is an important finding because treatment is anticoagulation, and failure to
treat may lead to insidious loss of kidney function despite adequately addressing
immune-complex LN with immunosuppression.20 (3) As discussed previously, it is diffi-
cult to predict the extent of renal histologic activity or chronicity using only clinical infor-
mation such as serum creatinine, level of proteinuria, or urine analysis.21,22 The balance
between activity (glomerular neutrophils, necrosis, endocapillary hypercellularity,
cellular crescents, interstitial inflammation) and chronicity (glomerulosclerosis, fibrous
crescents, interstitial fibrosis, tubular atrophy) dictates whether to immunosuppress or
to use kidney-protective therapies such as strict blood pressure control, sodium re-
striction, and inhibitors of the renin-angiotensin-aldosterone system.23 (4) Several
novel biologics have been tested and failed as therapies for LN, and more are in devel-
opment.24 A factor contributing to these failures may be the heterogeneity of LN. Suc-
cess with the new, highly specific agents may be limited to certain subsets of patients
with LN, and the kidney biopsy is likely to be required to identify responsive patients.
540 Rovin et al
3. A diagnostic kidney biopsy and a follow-up biopsy during treatment should be

routinely done in patients with LN.
The data on repeat biopsies for LN come from studies that have been done for clin-
ical indications (ie, for patients with LN who did not respond to therapy as expected)
and from protocol biopsy studies in which the repeat biopsy was done after induction
or maintenance therapy to determine the effect of treatment on kidney histology.
These investigations have provided important information on the prognostic value of
the kidney biopsy for long-term renal health, and a time line of the renal histologic
response to treatment.
Protocol biopsies performed after 6 to 9 months of induction therapy in adults and
children have shown that the second biopsy is more predictive of long-term patient
and kidney outcomes than the initial biopsy.10,11,25 In adults, the findings at the
6-month biopsy that predicted a doubling of serum creatinine (a surrogate for end-
stage kidney disease) after a mean follow-up of 7.6 years were ongoing glomerular
and interstitial inflammation, ongoing presence of glomerular capillary immune com-
plexes, and the presence of macrophages in tubular lumens.10,25 The extent of chro-
nicity on the second biopsy did not predict long-term outcome. Other studies reported
on the relationship between repeat kidney biopsies a year or more after completion of
induction therapy and kidney outcomes 7 to 8 years later.26,27 The activity index4 on
the repeat biopsy, persistent glomerular and tubulointerstitial inflammation, and
persistent or worsening of subendothelial immune-complex deposits were predictive
of poor long-term outcomes such as doubling of serum creatinine, renal impairment,
or death.
One potential confounding issue in all of these studies is that treatment after the
second biopsy was not standardized and/or not described. Therefore it is not possible
to determine the impact of treatment decisions on long-term kidney outcomes, or how
treatment affects the predictive value of these pathologic findings. Nonetheless, it is
reassuring that different cohorts, undergoing second biopsies at different intervals,
found similar pathologic predictors of renal deterioration.
Protocol repeat biopsy studies also show how the kidney responds to treatment.
Second biopsies done directly after induction therapy with corticosteroids, plus a cyto-
toxic agent or antimetabolite, generally show a decline in active lesions, but an in-
crease in scarring lesions.28 There is seldom complete histologic remission after
induction therapy. However, some patients did not show active lesions after induction,
which raises the question of whether they need further maintenance immunosuppres-
sion.10,28 There are no data to answer this question, and focal active lesions could have
been missed on the biopsy, but, if studied prospectively and such patients did well
without ongoing treatment, there would be a strong argument for performing a second
biopsy after initial treatment to see who could immediately stop further toxic therapy.
Repeat biopsy studies in which the second biopsy was done after several years
(1.5–4.7 years) of treatment are even more informative than repeat biopsies done after
induction.26,27,29–31 After prolonged standard-of-care treatment, 30% to 77% of pa-
tients still had persistent proliferative or class V LN. More concerning, 30% to 60%
of patients with complete clinical renal response had persistent histologic activity,
including glomerular and tubulointerstitial inflammation and subendothelial immune
deposits.26,31 As discussed previously, these histologic findings at repeat biopsy
have been associated with poor long-term kidney outcomes. These data reinforce
the known discordance between clinical measures of remission and histologic remis-
sion, and raise the question of whether a repeat biopsy is needed to define LN remis-
sion. The concept of histologic remission is also applicable to patients who have been
treated aggressively but have persistent proteinuria. A recent repeat biopsy investiga-
tion showed that several such patients had no residual histologic activity, and,
although not considered to be complete responders on clinical grounds, seemed to
be complete responders histologically.32
Repeat biopsies for clinical indications have been done to assess LN flares or to
determine why patients have not responded to treatment.30,33,34 Some investigators
have suggested that the decision to repeat a biopsy at LN flare should be based on
the LN class on the initial biopsy.35 Class switch in LN is common,22,35 but a class
switch from a proliferative lesion to a pure nonproliferative class is less common.35
Thus patients who have a nonproliferative LN class at baseline biopsy are more likely
to benefit from a repeat biopsy. In general, most reports conclude that the information
gathered from repeat biopsies in patients doing poorly has been useful in deciding
further management.
Synthesizing all of these data, Fig. 2 presents our suggested algorithm of when to
do a kidney biopsy in patients with LN.
BIOMARKERS OF KIDNEY DISORDERS
LN is so intrinsically heterogeneous it is difficult to adequately convey what is seen on

kidney biopsy using only standard classification terminology. LN classes are divided
into active, active plus chronic, and chronic, and lesions into global and segmental.
Active raises a spectrum of lesions including endocapillary hypercellularity, subendo-
thelial immune complexes, crescents, and/or glomerular capillary necrosis. Likewise,
SLE Paent Develops New:

• Proteinuria (≥ 500 mg/d)
• Glomerular Hematuria (especially in
combinaon with proteinuria)
• Renal Insuﬃciency (aributable to SLE)
PERFORM KIDNEY BIOPSY
Inducon and
Maintenance Treatment
No Renal Paral Renal Complete

Stop Therapy?
Response Response Renal Response
REPEAT KIDNEY BIOPSY
REPEAT KIDNEY
BIOPSY Modify Therapy? CONSIDER REPEAT KIDNEY
REPEAT KIDNEY LN Flare BIOPSY
BIOPSY
Fig. 2. Algorithm for kidney biopsy in LN. A diagnostic kidney biopsy should be done to
guide therapy when a patient with lupus presents with clinical evidence of new kidney
injury. A repeat biopsy should be done to confirm complete histologic remission in patients
who have achieved complete clinical renal response so maintenance immunosuppression
may be stopped. A repeat biopsy should be done to guide changes in therapy for patients
who have incompletely responded. A repeat kidney biopsy should be considered at LN flare
if there is suspicion that histology has changed and therapy may need to be modified.
542 Rovin et al
chronic connotes glomerulosclerosis, fibrous crescents, interstitial fibrosis, and/or

tubular atrophy. Thus a pathologic diagnosis of class IV-G (A/C) must be accompanied
by a description of what was seen under the microscope. Complicating the heteroge-
neity of LN is that the lesions evolve over time, classes change, and patients are not
uniformly identified at a specific stage. Therefore, biomarkers that noninvasively iden-
tify the presence (or absence) and severity of specific pathologic lesions are likely to
be more useful for prognostic and treatment decisions than biomarkers that identify a
specific LN class. Such biomarkers are applicable across LN classes and individual
patients. Nonetheless, many investigators have focused on identifying biomarkers
to noninvasively diagnose LN class (Table 1).
For all the reasons outlined previously, lesion-specific biomarkers are not intended
to preclude a diagnostic kidney biopsy when LN is first suspected. Rather, lesion-
specific biomarkers are expected to be used to monitor changes in kidney injury in
real time, as a noninvasive equivalent of serial kidney biopsies (Fig. 3). The prospective
assessment of kidney histology during treatment would allow therapy to be modified
to account for tissue response, facilitating personalized titration of immunosuppres-
sive agents. Improved kidney outcomes and less therapeutic toxicity would be
expected to result from such personalization. Furthermore, a biomarker-based treat-
ment platform could help refine the definition of complete and partial renal response
beyond the arbitrary levels of proteinuria and serum creatinine used currently (see
Fig. 3). In addition, it is conceivable that following pathology biomarkers prospectively
after a renal response could provide an early warning of increasing kidney inflamma-
tion, allowing preemptive intervention to avoid a full-blown LN flare (see Fig. 3).
Because the percutaneous needle biopsy is the gold standard for renal pathology,
biomarkers of disorders will have to approach the same level of accuracy to be
accepted clinically. To estimate accuracy, needle biopsies were done at the time of
autopsy in patients with and without kidney disease (n 5 103).36 Overall, the needle
biopsy agreed with the autopsy findings 84% of the time in diffuse disease, but only
51% of the time in focal disease. With respect to specific compartments, there was
96% agreement for glomerular lesions and 31% to 87.5% agreement for interstitial le-
sions. However, only 7 patients in this autopsy study had a glomerular disease, and
none of these were focal lesions. Because accuracy diminishes with focal disease,
glomerular accuracy may be less than 96% for LN. Other investigators estimated bi-
opsy accuracy as the theoretic misclassification rate assuming a binomial distribution
of abnormal glomeruli in the kidneys.37 This calculated misclassification rate was 25%
with 10 glomeruli and 15% with 20 glomeruli, but does not account for interstitial le-
sions. The misclassification rate of chronic allograft nephropathy, a tubulointerstitial
disease found in transplanted kidneys, was not influenced by number of glomeruli,
and was 12% in one study.38
In summary, a misclassification rate of 10% to 20% may be acceptable for bio-
markers of kidney disorders in LN, especially when considering focal lesions and inter-
stitial disease. It is conceivable that urine-based biomarkers are more accurate than
needle biopsies, because urine analytes presumably represent lesions throughout
the kidneys and are therefore not subject to sampling error or inadequate sample
size. However, this is difficult to prove because biomarkers can only be directly
compared with needle biopsies.
A representative selection of putative LN kidney pathology biomarkers reported to
date is illustrated in Table 1. These include biomarkers that differentiate proliferative
and nonproliferative LN, biomarkers that differentiate between global levels of activity
and chronicity in the kidney, and biomarkers that identify the presence, absence, or
severity of specific pathologic lesions. Most of these biomarkers are serum or urine
Table 1
Biomarkers of kidney disorders in LN
Biomarker N Histologic Lesion R AUC Sensitivity (%) Specificity (%) PPV/NPV (%) Reference
28
Panel: serum C1q, 18 Presence of ongoing proliferative — — 100 100 100
albuminuria LN after induction
49
Urine CD41 cells 147 Presence of proliferative LN — 0.99 100 98 —
39
Urine taurine 14 Presence of class V LN — 1 100 100 —
Urine citrate 0.88 86 100
40
Panel: urine MCP-1, 76 Presence of high activity — 0.85 72 60 —
ceruloplasmin, a1-acid
glycoprotein
40
Panel: urine NGAL, MCP-1, 76 Presence of high chronicity — 0.83 73 67 —
and GFR
49
Anti-C1q autoantibodies 52 Correlates with glomerular: — — — — —
Endocapillary proliferation 0.3
Inflammation 0.42
Necrosis 0.3
Kidney Biopsy in Lupus Nephritis

49
Anti-C1q autoantibodies 52 Correlates with: — — — — —
Glomerular sclerosis 0.32
Interstitial fibrosis 0.39
44
Anti-C1q autoantibodies 63 Presence of glomerular necrosis — — 100 31 37/100
44
Anti-C1q autoantibodies 63 Presence of glomerular crescents — — 92 31 45/86
41
Panel: urine MCP-1, serum 61 Differentiates between levels of — 0.92 100 83 68/100
creatinine interstitial inflammation
Abbreviations: AUC, area under the receiver-operating characteristic curve; C1q, fragment of the first component of complement; GFR, glomerular filtration rate;
MCP-1, monocyte chemotactic protein-1; NGAL, neutrophil gelatinase-associated lipocalin; NPV, negative predictive value; PPV, positive predictive value; R, cor-
relation coefficient.
543
544 Rovin et al
Biomarkers of kidney pathology
Resolve Adjust Surveillance for

discordance medicaƟons inflammaƟon pre-
between renal conƟnuously flare
pathology and
clinical measures
Refine renal
ena Follow response
ponse IniƟate trea
treatment
response criteria; conƟnuously and respond pre-empƟvely to
prevent ongoing in real Ɵme to decrease prevent or shorten
kidney injury and duraƟon of kidney injury flare duraƟon
new flares
Prevent CKD/ESRD
Fig. 3. Application of biomarkers of kidney pathology in LN. The rationale for identifying
biomarkers of disorders and how these biomarkers are expected to improve the manage-
ment of LN are shown. In this schema the biomarkers of kidney disorders reflect the
presence and severity of specific lesions such as glomerular crescents, interstitial inflamma-
tion, or interstitial fibrosis. Lesion-specific biomarkers measured serially and frequently pro-
vide an understanding of how kidney injury evolves in real time during and after LN
treatment. CKD, chronic kidney disease; ESRD, end-stage renal disease.
proteins, although 1 study used urine metabolomic profiling to differentiate between

pure class V and proliferative LN,39 and another study used urine T-cell counts to
determine the presence of proliferative LN. Biomarkers can be single analytes or a
panel of analytes, although several investigations suggest that accuracy improves
when analyte panels are used.28,40–43 Some of the panels include nonspecific indica-
tors of kidney injury such as serum creatinine, glomerular filtration rate, and protein-
uria/albuminuria. Novel biomarkers are expected to bring added value to these
clinical measurements, and such combinations may yield robust composite bio-
markers. In addition, in multibiomarker panels, individual biomarkers most likely
contribute differentially to the composite biomarker. We have used linear discriminant
analysis to weight and combine individual biomarkers that are biologically plausible or
that have been identified as relevant to LN using unbiased screening techniques such
as urine proteomics.41 In this approach, the discriminant function is the composite
biomarker and takes the form of an equation in which urine and serum analyte mea-
surements are input, and the resulting calculated value differentiates between levels
of severity of specific histologic findings in LN kidneys.41 Such composite biomarkers
can readily be adapted to the clinical laboratory.
The clinical performance metrics of sensitivity, specificity, and area under the
receiver-operating characteristic curve are encouraging for several of the pathology
markers (see Table 1). The positive predictive values of the biomarkers are variable
but generally low, whereas the negative predictive values are uniformly good, suggest-
ing that these biomarkers may be most useful for excluding a particular disorder.
Misclassification rate is a key performance metric for novel biomarkers, and for these
markers it ranges from 0% to 49%. However, several markers have an accuracy of
80% to 90% in relation to the needle kidney biopsy.39,41,44
The pathology biomarkers presented in Table 1 seem to be diverse and unrelated,

but several are mediators of inflammation. It is informative to discuss a few of these
proposed markers. The first component of complement, C1q, and antibodies to
C1q are heavily represented in Table 1. The complement system plays a key role in
the pathogenesis of SLE, and virtually all patients with complete C1q deficiency
develop lupus or a lupuslike disease, and often severe LN.45,46 This tendency may
be caused by loss of the protective effect of C1q in mediating clearance of apoptotic
debris and immune complexes.46 However, most patients with SLE do not have C1q
deficiency and although the complement system can be protective it is also proinflam-
matory. C1q is almost always present in the glomeruli of patients with active LN.47
Glomerular C1q–anti-C1q immune complexes may focus complement activation to
glomeruli, amplifying kidney inflammation and injury,48 which is consistent with C1q
consumption and C1q autoantibodies as surrogate markers for proliferative (inflam-
matory) LN classes and inflammatory glomerular lesions (crescents, necrosis), and
the negative correlation of anti-C1q with chronic lesions (glomerulosclerosis, intersti-
tial fibrosis).28,44,49
Monocyte chemotactic protein-1 (MCP-1) is a proinflammatory chemokine that has
been shown to recruit inflammatory cells to the kidney in several types of nephritis
including LN.50,51 Blocking the activity of MCP-1 in animal models of LN ameliorates
kidney injury.52 In humans, MCP-1 is a specific biomarker of LN flare.53 It is therefore
expected that MCP-1 may be a marker of inflammatory disorders in LN.40,41 It may be
surprising that MCP-1 also contributes to a panel of biomarkers that is a surrogate for
chronic disorders,40 but macrophage infiltration into the kidney is necessary for gen-
eration of fibrosis. In addition, MCP-1 stimulates fibroblast and monocyte collagen
production, and monocyte expression of the profibrotic cytokine transforming growth
factor beta-1.54,55
Neutrophil gelatinase-associated lipocalin (NGAL) is a small, glycosylated protein
that acts as an epithelial growth and differentiation factor and belongs to a family of
proteins that are involved in cellular iron transport.56 Other iron regulatory proteins
such as transferrin and hepcidin have been identified as potential biomarkers of LN
activity, raising the possibility that iron availability may be involved in the pathogenesis
of kidney injury in LN, perhaps through redox signaling.57 NGAL is minimally
expressed in healthy kidneys, but in acute kidney injury caused by ischemia or inflam-
mation it increases in segments of the distal nephron.58 In a longitudinal pediatric LN
cohort, urine NGAL levels increased 3 to 6 months before LN flare, suggesting that it
may forecast flare.59 At present it is not clear whether NGAL is simply a marker of
tubular injury in LN and other kidney diseases or is directly involved in tissue injury.
There are some animal data suggesting that NGAL may even be tubuloprotective.56
Nonetheless, NGAL seems to be mainly associated with acute processes, which
seems inconsistent with NGAL being on a biomarker panel for biopsy chronicity.40
However, the primary data show that NGAL decreases in the chronicity panel.40
Although many of the biomarkers listed in Table 1 seem promising, none are ready
for clinical practice. Most were identified in small cross-sectional cohorts and have not
yet been verified in independent patient populations. After verifying reproducibility, it
would be ideal to clinically validate pathology biomarkers by testing how well they pro-
spectively track changes in kidney histology over time. The most direct way to do this
would be with serial kidney biopsies, but such a study would be excessively invasive.
An alternative trial design for clinical validation is shown in Fig. 4. This design tests
whether altering duration and intensity of standard induction and maintenance medi-
cations provides an advantage compared with usual management in terms of com-
plete response rate, LN flare rate, safety, and cumulative drug exposure.
546 Rovin et al
Adjust length and Stop maintenance

Begin standard
intensity of therapy based on
inducon
Biomarker- inducon based on biomarker response
therapy
based strategy biomarker response
Randomize Compare 12 month outcomes:

biopsy- Number of CRR, me to CRR, LN
diagnosed LN ﬂare rate, cumulave
paents immunosuppression, treatment
toxicies
Usual-care Standard
Standard
strategy inducon
maintenance
therapy for 6
therapy
months
Fig. 4. Clinical validation of kidney pathology biomarkers. Patients with biopsy-proven LN

are randomized to a usual-care treatment strategy or a biomarker-based treatment strategy.
The usual-care strategy follows the induction and maintenance recommendations of the
2013 ACR treatment guidelines. The biomarker-based arm begins treatment in the same
way, but duration and intensity of treatment are modified monthly based on how bio-
markers of active pathologic lesions are responding. For example, if biomarkers are normal-
izing, induction could be shortened and maintenance started early; if lesions are not
responding well, induction could be lengthened. Maintenance could be discontinued if
the biomarkers indicated a complete histologic remission. All patients are followed for
12 months and at that time outcomes between the arms are compared. The outcomes to
be measured are indicated in the figure. Complete renal response (CRR) is adjudicated clin-
ically from kidney function and proteinuria, as is currently done, and also compared with
complete histologic response.
MOLECULAR DIAGNOSIS: THE FUTURE OF THE PERCUTANEOUS KIDNEY BIOPSY IN LN
As discussed previously, LN is intrinsically heterogeneous. At present all patients diag-

nosed with a particular class of LN tend to be treated in a similar fashion. It is conceiv-
able that therapy would be more effective and less toxic if it specifically targeted the
pathogenic mechanisms actively involved in kidney injury at the time of diagnosis. This
possibility is especially relevant for novel therapies being trialed or developed for LN.
These new drugs generally work on limited areas of the immune system, so under-
standing the mechanisms at play in an individual patient with LN should facilitate
appropriate matching of novel therapies to patients likely to derive benefit, improving
outcomes, limiting side effects, and containing costs. Integration of molecular and his-
tologic evaluation of the kidney is feasible by applying-omic techniques to kidney
biopsies in LN.
Molecular analysis of the kidney presents several challenges. Clinical kidney bi-
opsies are small, providing little tissue for evaluation, and are often formalin fixed
and paraffin embedded. Protocols have recently been developed to facilitate tran-
scriptomic and proteomic analysis of the tissue left over from clinical kidney bi-
opsies.60–62 The architecture of the kidney adds to the complexity of molecular
analysis. The kidney is divided into glomerular and tubulointerstitial compartments,
and there are several distinct cell types within each compartment, including infiltrating
inflammatory cells in LN. The expression profile of inflammatory mediators may differ
between compartments. For example, glomerular T cells from class III and V LN bi-
opsies expressed Th1, Th2, and Th17 cytokines, whereas isolated interstitial T cells
expressed mainly Th2 and Th17 cytokines.63 Laser-capture microdissection (LCM)
of specific renal lesions from specific renal compartments, followed by RNA or protein
analysis, offers an approach to identify differentially expressed transcripts or proteins
that characterize the pathology and pathogenesis of LN lesions.
In an early application of these techniques, the molecular heterogeneity among pa-
tients with LN was convincingly shown. Glomeruli from kidney biopsies were isolated
by LCM and then analyzed by complementary DNA microarray for transcriptional phe-
notyping.64 Compared with normal kidney, 4 distinct transcriptional patterns emerged,
including increased expression of B-cell genes, myelomonocytic (macrophages and
dendritic cells) genes, type I interferon-inducible genes, and fibrosis-related genes.
The level of transcript expression varied considerably in glomeruli from different pa-
tients, but within a kidney transcript expression was surprisingly consistent between
glomeruli despite histologic variability. For example, individual biopsies could be
segregated into 2 broad groups based on the type I interferon-inducible and
fibrosis-related gene clusters. Biopsies with high levels of interferon-inducible genes
had low levels of fibrosis genes, whereas biopsies with high levels of fibrosis genes
had low levels of type I interferon-inducible genes. Although only some kidneys
showed increased glomerular expression of fibrosis-related genes, the expression
of such genes was similar in glomeruli from the same kidney, whether or not they
had histopathologic evidence of glomerulosclerosis. These findings show the difficulty
in personalizing LN treatment using only histologic information.
As discussed previously, diagnostic biopsies are not good predictors of future kid-
ney outcomes in LN. Examination of biopsy gene expression patterns may increase
their predictive value. Diagnostic biopsies from class III and IV LN were segregated
by renal response status an average of 11 months after standard induction and main-
tenance therapies (cyclophosphamide and MMF; Parikh and colleagues. Molecular
characterization of renal responses in lupus nephritis using serial kidney biopsies.
Poster; American Society of Nephrology, 2013). The expression of 511 immune
response genes was analyzed directly from the kidney biopsy cores by NanoString
technology.65 Using principal component analysis, the samples clustered by whether
the patients were complete responders, partial responders, or nonresponders (Fig. 5).
These results suggest that gene expression analysis of the diagnostic kidney biopsy
may identify patients who are likely to respond to conventional treatment before ther-
apy is started. Alternate therapy may then be considered for those who have an unfa-
vorable transcript response profile.
In addition to profiling differential gene expression, recent work showed that clinical
kidney biopsies could also be analyzed for differential protein expression using unbi-
ased proteomic techniques. Glomeruli and renal interstitium were isolated by LCM and
proteins extracted from these two compartments were identified by mass spectrom-
etry.62 Several differences between normal and LN kidneys were observed. As ex-
pected, class IV glomeruli showed increased levels of complement proteins and
decreased levels of antioxidant and podocyte proteins. Tissue proteomics showed
an increase in the protein products of interferon-alfa–inducible genes, consistent
with the lupus interferon-alfa signature shown by transcript analysis.62 Transcript
and protein analyses of kidney biopsies may thus be considered complimentary,
especially for designing novel drugs for LN. Expression studies focus attention on spe-
cific pathways for intervention, and differentially expressed proteins within these path-
ways may be particularly good therapeutic targets.
The molecular analysis of LN biopsies has generated, and will continue to generate,
large amounts of data. In an effort to organize these data in a mechanistically and ther-
apeutically useful way, disparate and large datasets are now being analyzed using a
systems biology approach. The objective of systems biology is to integrate complex
548 Rovin et al
Fig. 5. Principal component analysis (PCA) of kidney biopsy transcriptional profiles. RNA was
harvested from archived kidney biopsies performed at LN flare, and for which kidney out-
comes after treatment were known. Preimplantation living transplant donor biopsies
were considered normal. Immune gene expression was measured by NanoString technology.
PCA was done on the RNA expression data. PCA shows that, at renal flare, patients clustered
by the type of renal response they had long term. CR, complete renal responder; NR, nonre-
sponder; PR, partial renal responder.
biological information to acquire a comprehensive description of the molecular events

that lead to organ dysfunction.66 With respect to LN, clinical information and molecular
data from kidney biopsies can be combined to identify relevant pathogenic networks
in LN.
To exemplify the potential of a systems approach, transcriptional networks were
compared in murine and human LN.67 Murine models have provided significant insight
into the pathogenesis of LN but do not entirely recapitulate the events that occur in
human LN, which may explain the failure of murine therapies to translate to human
LN. Using LCM, tubulointerstitial regions were isolated from human LN kidney bi-
opsies and their transcriptional profiles determined. Using sophisticated bioinformatic
techniques, these were compared with the transcriptional profiles of whole kidneys
from 3 different murine models of LN. The investigators identified 20 transcriptional
networks that were similarly activated (or repressed) in human LN and all of the LN
mouse models.67 These networks included, but were not limited to, antigen presenta-
tion and dendritic cell maturation pathways, and interleukin-17, mitogen-activated
protein kinase, and interferon signaling pathways. Developing and testing novel LN
therapies in the mouse based on these common pathways may increase the likelihood
that the drugs will be effective for human LN.
SUMMARY
The available evidence suggests that the percutaneous kidney biopsy is still relevant to
the clinical management of LN. However, it is also clear that more information resides
within kidney biopsies than is available from histopathology alone. This information
can be released by molecular analysis of biopsies. Molecular analysis is feasible, and

promises to help personalize therapy and enhance drug discovery for LN.
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I m p ro v i n g P a r t i c i p a t i o n i n
C l i n i c a l Tri a l s o f N o v e l
T h e r a p i e s : Going Back to Basics
Chan-Bum Choi, MD, PhDa,b,c, Sang-Cheol Bae, MD, PhD, MPH
a
,
Samar Gupta, MDc, Malcolm P. Rogers, MDd,
Matthew H. Liang, MD, MPHc,*
KEYWORDS
Systemic lupus erythematosus Randomized clinical trials Enrollment Retention
KEY POINTS
Enrollment in most clinical trials has declined over time.
Strategies associated with higher enrollment rates are not well studied, in general, and
especially in systemic lupus erythematosus.
Improving outcomes has been replaced by improving the audit trail and documentation.
Refocusing the “ask,” realizing that most participants do not have adequate health liter-
acy, using principles of plain English, and understanding decision-making heuristics could
improve efficiency.
BACKGROUND
Since the first published clinical trial in the Book of Daniel,1 which compared plant and
water with meat and wine and their effect on physical appearance, the randomized
controlled clinical trial has become the gold standard of clinical research. Their num-
ber, size, oversight, time to completion, and costs have increased logarithmically even
as their power and influence have eroded2 and the calls for reform are mounting.3
One disturbing sign is that more than 81% of recent clinical trials experience delays
from poor recruitment.4 One of 5 subjects recruited never show up for screening; one
of 20 subjects enrolled do not complete the trial.5 Both recruitment and enrollment
rates seem to be getting worse. The rate of enrollment was 75% between 1999 and
2002 and 59% in 2003 and 2006; retention was 69% between 1999 and 2002 and
Supported in part by Hanyang University.

a
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul,
Republic of Korea; b Department of Aging, Brigham and Women’s Hospital, Boston, MA,
USA; c Section of Rheumatology, VA Healthcare System, Boston, MA, USA; d Tufts University,
Boston, MA, USA
E-mail address: MHLIANG@PARTNERS.ORG

0889-857X/14/$ – see front matter Published by Elsevier Inc.
554 Choi et al
decreased to 48% between 2003 and 2006.5 Delayed enrollment of more than a
month is experienced in 70% of the trials in the United States,4 causing delays in
completion of the trials and higher costs.5 For one academic center, the annual cost
of desultory enrollment was almost a million dollars.6
DETERMINANTS OF THE PHENOMENA
Several factors are at play. Some are of special relevance for systemic lupus erythem-
atous (SLE) trials.7 The general factors include the growth of the contract research
organization industry,8 increasing oversight, and distrust of the research enterprise
from high-profile scientific misconduct and fraud.
In SLE trials, factors limiting higher enrollment rates, in addition, include overesti-
mating the number of potentially eligible subjects (the Lasagna rule or Feinstein
rule), logistical and entry criteria, participant burden, and the fear that a change in ther-
apy may cause a lupus flare. Whatever the reason, potential subjects are voting with
their feet and, after weighing the potential gains, downsides, and their personal prior-
ities, have decided not to get involved. What’s wrong? What can be done about it?
This trend is a signal that the current trials in SLE may not be serving patients well
nor those committed to developing new treatments.
There are many reasons to participate in a study, but it only takes one reason for a
person not to participate. Most decisions are driven by emotions. Some questions
going through a person’s mind when approached for a clinical trial might be whether
the question is really important to them, what is involved for the participating subjects,
whether they would lose their doctor, what they have to lose and the risk involved, and
what they can expect to get out of participation.
A “no” can be from the fear of losing their doctor for the study investigator, fear of
being a guinea pig or experimental subject, fear of flare, being too sick, being too busy
to be participating in a clinical trial that seems too complicated and too long, or not
understanding and feeling anxious about a consent form that is inscrutable, compli-
cated, and in legalese.
REVIEW OF LITERATURE ON MAXIMIZING ENROLLMENT/RETENTION
The literature addresses techniques or practices to maximize enrollment and reten-

tion; these are the subject of a Cochrane Review.9 Three techniques have been iden-
tified, in addition, on SLE drugs trials, 2 of which are on preventing vascular disease in
SLE.10,11 This discussion builds on the third, a review of Ferland and Fortin discussing
the issue in a controlled trial of methotrexate therapy for SLE.12
The literature indicates that subjects with good general health status are more likely to
enroll because they feel less anxious about the possibility of worsening as a result of
participation in clinical trials and are unlikely to have exclusions from other comorbid ill-
nesses or laboratory abnormalities. Encouragement from their physician, desire to learn
about their condition, the use of “opting out” of contact with the study recruitment effort,
and financial incentives at invitation can increase enrollment. A well-established
network of physicians and investigators can also be helpful. Subjects are more likely
to join open-labeled trials than blinded trials with placebo as a possibility.
What has not generally been successful in increasing enrollment are implementing
certain kind of changes to the consent procedures and giving more information. The
opt-out method whereby the patient must contact the investigator if they chose not
to participate yields more subjects than a trial that requires the subject to contact
the investigator if they wanted to participate (opt-in).13 However, local institutional
review boards differ on what is acceptable. Consent procedures, such as getting
Improving Participation in Clinical Trials 555
consent for experimental or standard therapy, allowing patients to choose either

experimental or standard therapy if they refuse to be randomized, and informing
that they had more chance of being in the experimental group, were not successful
in improving recruitment.14,15
Things that might increase participation are testimonials from existing participants,
training recruiters, and having the person’s physician involved with recruitment. On
this latter point, US Institutional Review Boards vary in their view of whether the pri-
mary care physician or physician of record can ethically recruit their own patient,
some thinking that having physicians recruit their own patients is an inherent conflict
and/or potentially coercive.
What works and is only limited by the resources available include many items in the
typical menu of services provided by contract research organizations: extra-dedicated
staff, financial incentives with invitation, telephone reminders to nonresponders to
written invitations, taking care of logistical concerns, such as parking, lack of time,
and child care. In addition, the nation is in the middle of a sea of change of health
care financing and trials participation and costs will very likely be influenced by the in-
dividual’s residence and a state’s adherence to insurance coverage of clinical trials
under the Accountable Care Act of 2010.
RECOMMENDATIONS
To improve recruitment and retention, it is useful to view the challenge of enrolling sub-
jects in SLE from the point of view of someone with SLE. Their physicians have empha-
sized the need for regular indefinite follow-up; that lupus can be unpredictable,
chronic, life-threatening and potentially fatal; that lupus can affect any organ. The pa-
tient has often experienced the high and the magical response to steroids, also its
many toxicities, and for women especially, every possible effect on their appearance
and sense of attractiveness. Having lupus, like all chronic diseases, is like having yet
another full-time job, a horrible drag. Now someone is asking them to participate in an
“experiment” like “a flip of a coin” to see what will happen.
The typical enrollment procedures of a clinical trial are about managing risk and threats
to rigor. Each requirement in the aggregate reduces the pool of eligible persons, dimin-
ishes generalizability, and reduces the likelihood of blame and litigation, all unproven.
As a consequence, the checklist of doing trials has increased and many items of the
checklist are delegated to the least clinically involved persons with the patient and are
removed from the ultimate goal of improving outcomes for persons. We have lost our
way and replaced the real goal for the minutiae of establishing the audit trail. We have
forgotten to ask the patient permission for their help, to appreciate their sacrifice and
assistance, to respect their time, to express the ignorance that drives our ambition to
do better.
No one can argue the importance of an informed consent in recruiting a patient into
a clinical trial, but the form itself, typically, is more than 20 pages in many studies, often
unintelligible, unreadable, and complicated. Dr Daniel Federman’s rules for being an
effective physician: listen well; keep it simple; think out loud; and be kind as is appli-
cable to relating to study subjects. The authors suggest the following.
Keep It Simple
Keep trial designs simple for the potential participant. Simple trials should have min-
imal eligibility with as few inclusion and exclusion criteria as possible. Instead, one
should collect these clinical features, treat them as covariates, and deal with them
in the analysis.
556 Choi et al
Communicate Using Plain English

Communicate the goals and requirements of the trial to potential participants with an
appreciation of the rarity of health literacy. Use plain English. Appreciate how people
make difficult decisions when there is complexity and uncertainty and many factors to
juggle.
Only 12% of the population is proficient in health literacy with “the capacity to
obtain, process, and understand basic health information and services needed
to make appropriate health decisions.”16,17 Health literacy is not simply the ability
to read nor necessarily related to years of education or general reading ability. A
person who functions adequately at home or work may have marginal or inadequate
literacy in a health care environment. Health literacy also subsumes listening,
analytical, and decision-making skills, and applying these skills to participation in
clinical research. For example, it includes the ability to understand the purpose
and the design of evaluative studies, risks and harms, the precise treatment being
studied, and the protocol. Low health literacy is relevant to both the presentation of
the choice to participate in a clinical trial and the navigation of the research
protocol.18,19
Plain English (or plain language) is communication that is easily understood by the
target audience: clear and straightforward, appropriate to their reading skills and
knowledge, and free of wordiness, cliché, and needless jargon. The important lesson
for improving communication about trials is that plain English is more effective over the
entire range of educational attainment and in health even when the patient is a
physician.
Address the Factors Underlying Difficult Choices

The 2002 Nobel Prize in Economic Sciences honored Daniel Kahneman for “integrated
insights from psychological research into economic science, especially concerning
human judgment and decision-making under uncertainty,” the universal heuristics
used in making difficult decisions.20,21 Some of these are of particular relevance to
the dilemma facing persons being approached for a health experiment. Understanding
these heuristics gives insights on what would make the consent discussion more
useful. The Availability Bias is particularly germane to the consent process: the bias
occurs in decisions with complexity: individuals focus on things more familiar or avail-
able in their memory to drive their choice. Availability and immediacy might be based
on their last experience, the most intuitive, the worst case scenario of someone
familiar to them, or might be focused on the most easily understood concept or con-
cepts from a myriad of possible elements. Persons focus more on changes in their
utility-states than on absolute utilities. The lesson for trialists is that stating the harms
and benefits can and should be less off-putting and more aligned to what we are really
trying to accomplish.
Align “Ask” with Honest Emotion and Feelings

I’ve learned that people will forget what you said, people will forget what you did,
but people will never forget how you made them feel.
—Maya Angelou
Trials of novel therapies for SLE cannot be placebo controlled and for all intended
purposes are closer to a comparative effectiveness than an efficacy trial. The authors
recommend a different script for the enrollment process and ask the readers to
compare it to the usual “ask” underscored by technically correct many-page consent
forms of little use for communicating the real purpose (Table 1).
Table 1
Enrollment script based on ask versus feeling/meaning
Ask Feeling/Meaning
“Most of our treatments for SLE are not We really don’t know the best treatment for
evaluated well. All treatment can have side many kinds of lupus. Some treatments
effects.” (particularly steroids) work but can cause
These can be serious, happen right away, or serious problems.
over time. We need to do this together. I need you to
We don’t really know who will improve with help me help you.
any given therapy. We want to find out as soon as possible and
Will you help us to. try something else if this is not working or
you have problems.
You are in control.
For a superiority trial, in addition Find out which therapy works best, the
quickest, and with the least amount of side
effects.
For an equivalence trial, in addition Find out which therapy works with the least
amount of side effects.
For a steroid-sparing trial, in addition Find out the fastest way to get you off
steroids or on the least amount possible.
Minimize Time on Ineffective or Marginally Effective Treatments

The investigator desires retention of as many participants as possible and for as long
as possible to collect the most informative data. A treating physician would be foolish
to keep someone on a treatment that is not working or not well tolerated. The SLE
participant experiences the burden of following a protocol, and the amount of time
in a symptomatic and uncertain outcome state and does not want to stay on anything
that is not working. Setting a priori treatment effects that are meaningful to the clinician
and to the patient and defining the time to achieve this response is a way to limit expo-
sure and improve the efficiency of the study. Single cross-over designs, adaptive de-
signs, and escape treatment are means to accomplish this and should be used more
often.
Waste No Time
In attempting to recruit a subject in a trial, usually any hesitation is eventually a refusal.
Do not take it personally, nor persist. Determine interest through self-assessed means
first; it is more honest than an answer during a personal contact. Keep track of the
number of all contacts made because this is invaluable information for future budget-
ing and improving the efficiency of the study.
Learn from Refusals

An honest discussion without judgment and affirming the many reasons why participa-
tion is not a priority can help tweak a protocol. Do not delegate this. Do this early and
often and take every feedback seriously as an opportunity to improve the experience
of the study for the participant.
SUMMARY
In summary, publicly available data show that participant enrollments are down across
a range of diseases. A clear secular trend from controlled trials in SLE cannot be docu-
mented, the number of trials in novel treatments being relatively small until a decade
558 Choi et al
ago. The studies on what can be done to rectify this in general and in SLE are also
scant.
Everybody would probably agree that the costs and time have grown and for what-
ever the reasons indicate a problem. Potential eligible subjects, after weighing the po-
tential gains, downsides, and their own priorities, have decided not to get involved.
Refusals are an opportunity to rethink the process and improve the outcome.
We could do more to understand what factors are particularly important to SLE pa-
tients using qualitative methods and key informants. We must also avoid logistical bar-
riers, correct conceptual misunderstandings, and in explaining the study, avoid
needless complexity in their design and conduct and to do it in plain English.
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I ndex
Note: Page numbers of article titles are in boldface type.
A
Abatacept, 445–446
ABIN1 gene, 421
ACCESS (Abatacept and Cyclophosphamide Combination Efficacy and Safety Study),
445–446
Acetretin, 463
ACP5 gene, 414
Adipocytokines, 479
Adiponectin, 480
AFFI gene, 418
Albuminuria, 543
Alitretinoin, 463
ALMS (Aspreva Lupus Management Study) trial, 442–445, 527–530
AMG 811, 464
Angiotensin receptor blockers, 483–484
Angiotensin-converting enzyme inhibitors, 483–484
Annexin, 480
Antigen presentation, 419
Antihypertensives, 483–484
Antimalarials, 462–463, 485
Antiphospholipid antibodies, 478, 480
APOL1 gene, 421
Apoptosis, 414, 457–458, 499
APPLE (Atherosclerosis Prevention in Pediatric Lupus Erythematosus) trial,
484–485
Apremilast, 463
Aspreva Lupus Management Study (ALMS) trial, 442–445, 527–530
ATG5 gene, 414
Atherosclerosis, 475–495
biomarkers for, 478–482
drugs inducing, 485–486
pathogenesis of, 476
risk factors for, 477–478, 480–481
subclinical measures of, 482–483
treatment of, 483–484
Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial,
484–485
Atorvastatin, 484
Autoantibodies, 419, 461, 481, 543
Autoimmune lymphoproliferatve syndrome, 499
Azathioprine, 444–445, 485, 523–525, 530

http://dx.doi.org/10.1016/S0889-857X(14)00055-6 rheumatic.theclinics.com
0889-857X/14/$ – see front matter ª 2014 Elsevier Inc. All rights reserved.
562 Index
B
B cells, in pathogenesis, 461
BAFF, 459
Baltimore Lupus Environmental Study, 403
BANK1 gene, 418–420
B-cell immunity, 418
B-cell–targeted therapy, 445
BCL2 gene, 498
Belimumab, 445, 464, 507–517
Biological therapy, 445–446
Biomarkers
for atherosclerosis, 478–482
for kidney disorders, 541–546
Biopsy, kidney, 537–552
BLISS (Study of Belimumab in Subjects With Systemic Lupus Erythematosus) trial,
445, 507–517
B-lymphocyte stimulator, 459
BlyS, 459
Breast cancer, 501–502
C
Calcineurin inhibitors, 524
Cancer, 497–506
cervical, 500–501
head and neck, 501
hematologic, 498–500
lung, 500
types with decreased incidence, 501–502
Cardiovascular disease, atherosclerosis causing, 475–495
Carolina Lupus (CLU) study, 435
Cervical cancer and dysplasia, 500–501
Chemical exposures, 406–407, 458
Chemokines, 460
Chloroquine, 462–463
Cigarette smoking. See Smoking.
Clinical trials
for lupus nephritis, 519–535
for SLE, improving participation in, 553–559
CLU (Carolina Lupus) study, 435
Communication, for clinical trial recruitment, 556
Complement, 461, 545
Copy number variations, 422
Corticosteroids, 462, 485, 531
Costimuation blockers, 445–446
C-reactive protein, 478, 480
CTLA4 gene, 457
Cutaneous systemic lupus erythematosus
clinical manifestations of, 455–456
immunopathology of, 455–474
adaptive immune system in, 460–461
Index 563
innate immune system in, 461–462

therapeutic implications of, 462–464
triggers, 456–460
treatment of, 462–464
CXCL chemokines, 460
Cyclophosphamide, 442–446, 499–500, 521–532
Cyclosporine, 523–524, 530
Cytokines, as SLE triggers, 458–460
Cytomegalovirus infections, 457
D
Dendritic cells, 461
Dialysis, 446–447
Dietary factors, 403
Disability, work, 439
Diuretics, 484
DNA degradation, 414
DNase genes, 414
Drugs, as SLE triggers, 458
Dutch Working Party Trial, 523–525
E
EBNA1, 405
Endometrial cancer, 501–502
Environmental factors, 401–412
diet, 403
epigenetics and, 402–403
established, 403–405
genetics and, 402–403
less established, 406–407
study limitations for, 407–408
Epigenetics, environmental factors and, 402–403
Epstein-Barr virus infections, 405, 457, 499
Estrogen, 458
Ethnicity and race, 433–454
damage accrual and, 438–439
definitions of, 433–434
disease activity and, 435, 438
disease expression and, 434–437
mortality in, 440–442
statistics on, 433–434
therapy response and, 442–447
work disability and, 439
ETS1 gene, 414, 418
EULAR (European League Against Rheumatism), 483–484
Euro-Lupus Nephritis Trial, 446, 521–523
European League Against Rheumatism (EULAR), 483–484
EXPLORER (Exploratory Phase II/III SLE Evaluation of Rituximab) study, 445
Exposome, SLE, 408
564 Index
F
Fas gene, 499
Fc gamma receptors, 414, 418, 421
FVL gene, 419
G
Genetics, 413–432
autoantibody production, 419
cancer risk and, 498–500
clinical subsets and, 419–420
environmental factors and, 402–403, 405
of cutaneous SLE, 456–457
of nephritis, 420–421
pathogenic pathways in, 414–419
studies in progress, 421–422
Genome-wide association studies, 421–422
GLADEL (Grupo Latinoamericano de Estudio del Lupus or Latin American Group for
the Study of Lupus) cohort, 434–440
Glomerular Disease Collaborative Network, 442
Grupo Latinoamericano de Estudio del Lupus or Latin American Group for the Study of
Lupus (GLADEL) cohort, 434–440
H
Head and neck cancer, 501
Hematologic cancer, 498–500
Hematuria, 538–539, 544
Hemodialysis, 446–447
Hepatitis C, 457
Homocysteine, 479–480, 482
Hopkins Lupus cohort, 440
Hormones, as SLE triggers, 458
Human leukocyte antigens, 418–419, 456–457
Human papillomavirus infections, 500–501
Hydroxychloroquine, 462–463, 485
Hypertension, 483–484
I
IFIH1 gene, 418
IKZF gene, 418
Immunoglobulin, intravenous, 464
Immunopathology, 455–474
Immunosuppressive therapy, 463–464
Infections, 457
Inflammation, in atherosclerosis, 476
Innate immunity, 414, 418, 461–462
Interferons(s), 458–459, 481
Interleukin(s), 418, 459–460
Index 565
IRAK1 gene, 414

IRF5 gene, 457
IRF8 gene, 414, 418–419
IRF7/PHRF1 gene, 414
Isotretinoin, 463
ITGAM gene, 414, 418–419
J
JAK inhibitors, 463
K
K1AA1542 gene, 419
Kidney
biopsy of, 537–552
biomarkers and, 541–546
frequency of, 538–541
molecular studies of, 546–548
nephritis of. See Lupus nephritis.
transplantation of, 446–447
L
Lead exposure, 406
Lenalidomide, 463
Leptin, 479, 481
Lipoproteins
disorders of, 476
high-density, 476, 478–479
LUMINA (Lupus in Minorities: Nature vs. Nurture) study, 433–441
LUNAR (Lupus Nephritis Assessment with Rituximab) study, 445, 531
Lung cancer, 500
Lupus autoantibodies, 502
Lupus in Minorities: Nature vs. Nurture (LUMINA) study, 433–441
Lupus nephritis
biopsy for, 537–552
clinical course of, 520
ethnic factors in, 434, 440–447
genetics of, 420–421
membranous, 531
pathology of, 541–546
prognosis for, 520
treatment of, clinical trials in, 519–535
Lupus Nephritis Assessment with Rituximab (LUNAR) study, 445, 531
Lymphocyte development, 418
Lymphoma, 498–499
M
MAINTAIN (Mycophenolate Mofetil versus Azathioprine for Maintenance Therapy of
Lupus Nephritis) trial, 444–445, 530
566 Index
Major histocompatibility complex, 456–457

Malignancy. See Cancer.
Mercury exposure, 406
Metal exposure, 406
Methotrexate, 463
Miami study, 528
MIF gene, 420
Molecular analysis, in lupus nephritis, 545–546
Monoclonal antibodies, 464
Monocyte chemotactic protein, 543, 545
Monocyte signaling, 418
MTHFR gene, 419
Mycophenolate mofetil, 442–446, 485–486, 524, 526–530
Mycophenolate Mofetil versus Azathioprine for Maintenance Therapy of Lupus
Nephritis (MAINTAIN) trial, 444–445, 530
Myeloablative regimen, 523
N
NCF2 gene, 418
Nephritis. See Lupus nephritis.
NETosis, 461–462
Neutrophil(s), 418, 461–462
Neutrophil extracellular traps, 461–462
Neutrophil gelatinase-associated lipocalin, 545
Nuclear factor kappa beta signaling, 414
Nurses Health Study, 403
Nutrition, 403
O
Occupational exposures, 406
Organic pollutants, 406–407
P
Paraoxonase, 479
Persistent organic pollutants, 406–407
Pesticide exposure, 406–407
Photosensitivity, 457, 462
PHRF1 gene, 419
PRCKB gene, 414, 418
PRDM1 gene, 418
PREDICTS (Predictors of Risk for Elevated Flares, Damage Progression and Increased
Cardiovascular Disease in SLE), 482
Prednisone, 485
Pregnancy, 458
Prostate cancer, 501–502
Proteinuria, 538–539, 544
PTPN22 gene, 418–419
Pyuria, 538
Index 567
Q
Quinacrine, 462–463
R
Race. See Ethnicity and race.
RasGRP3 gene, 418
Retinoids, 463
Rheumatoid arthritis, cancer risk in, 498
Rituximab, 445, 464, 531
S
Selectins, 480
Sifalilmumab, 464
Silica exposure, 404
Sirukumab, 464
Sjögren syndrome, 499
Skin manifestations. See Cutaneous systemic lupus erythematosus.
SLC115A4 gene, 414
SLE. See Systemic lupus erythematosus.
SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score, 435
SLICC (Systemic Lupus International Collaboration Clinics) cohort, 435, 498
Smoking, 404–405, 458, 500
STAT4 gene, 414, 418–419, 421
Statins, 484
Study of Belimumab in Subjects With Systemic Lupus Erythematosus (BLISS) trial,
445, 507–517
Systemic lupus erythematosus
atherosclerosis in, 475–495
clinical features of, 419–420, 434–439
cutaneous, 455–474
environmental factors in, 401–412
ethnicity and, 433–454
genetics of. See Genetics.
kidney biopsy for, 537–552
malignancies in, 487–506
mortality in, 440–442
pathogenesis of, 508
treatment of
belimumab for, 507–517
clinical trials for, 519–535, 553–559
cutaneous, 462–464
ethnic factors in, 442–447
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, 435
Systemic Lupus International Collaboration Clinics (SLICC) cohort, 435, 498
T
T cells
in pathogenesis, 460
regulatory, cancer risk and, 502
568 Index
Tacrolimus, 523–525
T-cell immunity, 418
Terbinafine, 458
Thalidomide, 463
TNFAIP3 gene, 414
TNFSF4 gene, 418, 420–421
TNIP1 gene, 414, 421
Tobacco use. See Smoking.
Tocilizumab, 464
Tofacitinib, 463
Toll-like receptors, 414, 418, 456–457, 462
TRAF3IP2 gene, 419
TRAIL and receptor, 459
Transplantation, kidney, 446–447
TREX1 gene, 414, 457
Tumor necrosis factor-a, 459
TYK2 gene, 457
TYR2 gene, 418
U
UBE2L3 gene, 414, 419
Ubiquitination, 414
Ultraviolet light, 457
V
Vitamin D deficiency, 403, 405–406, 481
von Willebrand factor, 481
W
Work disability, 439

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Systemic Lupus Erythematosus

ELLEN M. GINZLER, MD, MPH

MARY ANNE DOOLEY, MD, MPH

GRACIELA S. ALARCÓN, MD, MPH, MACR

ANCA D. ASKANASE, MD, MPH

SANG-CHEOL BAE, MD, PhD, MPH

SASHA BERNATSKY, MD, PhD

CHAN-BUM CHOI, MD, PhD

ANN E. CLARKE, MD, MSc

LUIS ALONSO GONZÁLEZ, MD

JUDITH A. JAMES, MD, PhD

DIANE L. KAMEN, MD, MS

MARK G. KIRCHHOF, MD, PhD

MATTHEW H. LIANG, MD, MPH

MAUREEN MCMAHON, MD, MS

CHARLES T. MOLTA, MD, FACR

ROSALIND RAMSEY-GOLDMAN, MD, DrPh

BRIAN SKAGGS, PhD

SERGIO M.A. TOLOZA, MD

JINOOS YAZDANY, MD, MPH

Preface: Systemic Lupus Erythematosus xiii

Environmental Influences on Systemic Lupus Erythematosus Expression 401

Clinical Perspectives on Lupus Genetics: Advances and Opportunities 413

care and to provide care to these patients in a consistent manner regard-

The Immunopathology of Cutaneous Lupus Erythematosus 455

Pathogenesis and Treatment of Atherosclerosis in Lupus 475

Systemic Lupus Erythematosus and Malignancies: A Review Article 497

Post-marketing Experiences with Belimumab in the Treatment of SLE Patients 507

Recent Clinical Trials in Lupus Nephritis 519

The Kidney Biopsy in Lupus Nephritis: Is It Still Relevant? 537

RHEUMATIC DISEASE CLINICS

FORTHCOMING ISSUES RECENT ISSUES

Neurologic Clinics, February 2010 (Volume 28, Issue 1)

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Rheum Dis Clin N Am 40 (2014) xi

Ellen M. Ginzler, MD, MPH Mary Anne Dooley, MD, MPH

Rheum Dis Clin N Am 40 (2014) xiii–xiv

Ellen M. Ginzler, MD, MPH

Systemic lupus erythematosus (SLE) is a chronic and potentially severe systemic

Rheum Dis Clin N Am 40 (2014) 401–412

INTERPLAY BETWEEN ENVIRONMENTAL FACTORS, GENETICS, AND EPIGENETICS

DIETARY INFLUENCES ON SLE

ESTABLISHED ENVIRONMENTAL RISK FACTORS FOR SLE

A National Institute of Environmental Health Sciences (NIEHS) Expert Panel was

Silica Exposure and SLE

Cigarette Smoking and SLE

Smoking and the Role of Gene-Environment Interactions

EBV Exposure and SLE

INFLUENCE OF VITAMIN D STATUS ON SLE

Vitamin D, an essential steroid hormone with well-established effects on mineral meta-

LESS ESTABLISHED ENVIRONMENTAL RISK FACTORS

Pesticides, Persistent Organic Pollutants, and SLE

Other Environmental Agents and SLE

METHODOLOGICAL LIMITATIONS IN STUDIES OF ENVIRONMENTAL INFLUENCES

Although increasingly sensitive and specific biomarkers of exposure and disease

questionnaires to ascertain exposure and/or outcomes of interest. Cohort studies that

Defining the SLE Exposome

FUTURE CONSIDERATIONS AND SUMMARY

Despite a tremendous amount of progress in elucidating potential environmental risk

1. Somers EC, Marder W, Cagnoli P, et al. Population-based incidence and pre-

Conflict of Interest: The author declares no conflict of interest.

Rheum Dis Clin N Am 40 (2014) 413–432

Pathways Implicated by Lupus Genetics