Review

Lupus
0(0) 1–23
Systemic lupus erythematosus: The ! The Author(s) 2020
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DOI: 10.1177/0961203320979051
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Luis Alonso González1 , Manuel Francisco Ugarte-Gil2,3 and

on4,5
Graciela S Alarc

Abstract
During the last decades, there has been an increased interest in the discovery and validation of biomarkers that reliably
reflect specific aspects of lupus. Although many biomarkers have been developed, few of them have been validated and
used in clinical practice, but with unsatisfactory performances. Thus, there is still a need to rigorously validate many of
these novel promising biomarkers in large-scale longitudinal studies and also identify better biomarkers not only for
lupus diagnosis but also for monitoring and predicting upcoming flares and response to treatment. Besides serological
biomarkers, urinary and cerebrospinal fluid biomarkers have emerged for assessing both renal and central nervous
system involvement in systemic lupus erythematosus, respectively. Also, novel omics techniques help us to understand
the molecular basis of the disease and also allow the identification of novel biomarkers which may be potentially useful
for guiding new therapeutic targets.

Keywords
Systemic lupus erythematosus, biomarkers, autoantibody, complement, interferon, cytokine
Date received: 24 September 2020; accepted: 16 November 2020

Introduction Definitions: Biomarker and surrogate

Systemic lupus erythematosus (SLE) is the
prototypic multisystemic, autoimmune disease charac-
terized by heterogenous organ involvement and
the production of an array of autoantibodies. For
decades there has been considerable interest in bio-
markers research in SLE, but in current clinical
practice, only traditional biomarkers such as comple-
ment, anti-double-stranded DNA (dsDNA) antibodies,
white blood cell and lymphocyte counts, and urinalysis
remain as those used for the diagnosis and assessment
of disease activity, but with unsatisfactory performan-
ces. Due to the heterogeneity of immune dysregulation
in SLE, no single biomarker capable of predicting
susceptibility, diagnosis, disease activity, and response
to therapy has emerged. The objective of this review
is to examine the need for biomarkers in lupus,
summarize the search of reliable lupus biomarkers
for diagnosis, disease activity monitoring, and
specific organ involvement, and finally to present an
overview of the application of multi-omics in lupus
research.
marker
The terms biomarker and surrogate endpoint have
been used to describe biological measurements in
1
Division of Rheumatology, Department of Internal Medicine, School of
Medicine, Universidad de Antioquia, Hospital Universitario de San
Vicente Fundaci
on, Medell
ın, Colombia
2
Rheumatology Department, Hospital Guillermo Almenara Irigoyen,
EsSalud, Lima, Per
u
3
School of Medicine, Universidad Cient
ıfica del Sur, Lima, Per

u
4
Division of Clinical Immunology and Rheumatology, Department of
Medicine, School of Medicine, The University of Alabama at Birmingham,
Birmingham, AL, USA
5
Department of Medicine, School of Medicine, Universidad Peruana
Cayetano Heredia, Lima, Per
u
LAG, MFUG, and GSA are equal contributors.
Corresponding author:
Luis Alonso González, Division of Rheumatology, Department of Internal
Medicine, School of Medicine, Universidad de Antioquia, Hospital
Universitario de San Vicente Fundacio
n, Calle 64 # 51D-154, Medelli
n
050010, Colombia.
Email: alonso.gonzalez@udea.edu.co
2 Lupus 0(0)
therapeutic development and assessment. A biomarker
is a physical sign or cellular, biochemical, molecular, or
genetic feature by which a normal or abnormal biologic
process can be recognized and/or monitored and can be
evaluated qualitatively and/or quantitatively in labora-
tories. Laboratory biomarkers can be influenced by a
drug and have to be reliably measurable in tissues, cells,
and fluids. A surrogate end point is a marker that
intend to substitute for clinically meaningful outcome
that measures directly how a patient feels, functions or
survives. A surrogate endpoint is expected to predict
clinical benefit, lack of benefit or harm based on epi-
demiologic, therapeutic, pathophysiologic, or other sci-
entific evidence.1–3 All surrogate endpoints can be
considered biomarkers, but only a few biomarkers
will achieve the surrogate endpoint. For example,
some authors have considered histologic changes on
renal biopsy (tubular atrophy and interstitial fibrosis)
as a useful surrogate marker for clinical outcomes.3
The need for SLE biomarkers
SLE biomarkers are necessary for several reasons: (1)
misdiagnosis of SLE, even by experienced rheumatolo-
gists, can lead to therapeutic mistakes and life threat-
ening adverse drug reactions; (2) prompt recognition of
a lupus flare is of utmost importance as they may lead
to substantial organ/system damage, high morbidity
and mortality, and higher healthcare cost; (3) organ-
specific biomarkers would be useful to predict specific
flares (i.e., renal flares) and thus carrying out timely
preventive therapeutic strategies; (4) with the advent
of biological therapies, a pharmacodynamic biomarker
may help identifying patients who will respond favor-
ably to a particular compound and also to evaluate its
therapeutic efficacy, which would help reducing the
adverse effects of long-term therapy with glucocorti-
coids and immunosuppressants used in SLE
patients.4–6
The ideal biomarker for SLE
The search and validation of an ideal biomarker is one
of the main challenges in lupus research. This biomark-
er should have the following characteristics: (1) it must
be biologically and pathophysiologically relevant; (2) it
must provide validity, that is property characterized by
high predictive values, sensitivity and specificity to
reduce the probability of false positive or false negative
results; (3) it must have the ability to predict lupus
activity or flares before an obvious change in conven-
tional clinical parameters occurs; therefore, it can be
used for monitoring disease activity and considering
early treatment or preventive strategies; (4) it must be
reliably measurable in tissues, cells, or fluids; and, (5) it
must be easy to assay, interpret, and be readily avail-
able in most laboratories at a reasonable cost.6,7
However, due its complex pathogenesis, heterogeneous
clinical manifestations, and variable rates of disease
progression among SLE patients, a particular lupus
biomarker may be informative only about one specific
aspect of the disease, but not for all.6,8,9
Classification
The U.S Food and Drug Administration (FDA) and
the National Institutes of Health (NIH) Biomarker
Working Group defined and classified biomarkers
into different categories: diagnostic, monitoring, phar-
macodynamic/response, predictive, prognostic, safety,
and susceptibility/risk biomarkers.10 The types of bio-
markers, their definitions (FDA-NIH Biomarker
Working Group) and some examples in SLE clinical
settings are summarized in Table 1.10–19 Next, we will
focus on diagnostic, disease activity monitoring and
organ-specific lupus biomarkers.
Biomarkers for SLE diagnosis
The diagnosis of lupus is, still, clinical. The 1997-
revised American College of Rheumatology (ACR)
classification criteria,20 the 2012 revised Systemic
Lupus International Collaborating Clinics/American
College of Rheumatology (SLICC/ACR) classification
criteria,21 or the 2019 European League Against
Rheumatism (EULAR)/ACR Classification Criteria
for SLE22 are used for inclusion of patients in studies.
These criteria are not considered diagnostic but classi-
ficatory. So, the delay, oftentimes is related to the lim-
ited knowledge about lupus by primary care and other
physicians, the relative nonspecific nature of the symp-
toms and the fact that clinicians frequently use classi-
fication criteria for diagnosis, so they need the
fulfillment of such required criteria. In addition, overt
SLE is usually heralded by early serological findings,23
and antinuclear antibodies (ANAs), although positive
in 98% of SLE patients, they have a low specificity, as
they are also found in other autoimmune diseases,
malignancies, infectious diseases, or in up to 35% of
healthy individuals, especially if they are elderly.24,25
For these reasons, attention has been focused on dis-
covering other more specific biomarkers that facilitate
an early and accurate diagnosis of SLE.
In clinical practice, a few biomarkers highly specific
for SLE diagnosis are currently used [anti-dsDNA,
anti-Smith (anti-Sm), anti-ribosomal P (anti-P), com-
plement C3 and C4] while other biomarkers, also spe-
cific for SLE diagnosis, are not routinely used in
clinical practice as they still lack validation as a diag-
nostic tool in SLE [cell-bound complement activation
González et al. 3

Table 1. Types of biomarkers and their definitions according to the FDA-NIH Biomarker Working Group.10
Diagnostic
Definition: a biomarker used to detect or confirm the presence of a disease or condition of interest or to identify individuals with a
subtype of the disease.
Example in SLE: anti-Sm antibodies are highly specific biomarkers for SLE diagnosis (specificity, about 99%) but have a low sensitivity
(5–30%). They are virtually pathognomonic of SLE.11
Monitoring
Definition: a biomarker measured serially for assessing the status of a disease or medical condition or for evidence of exposure to
(or effect of) a medical product or an environmental agent.
Example in SLE: an increase in anti-C1q antibodies titer predicts renal flares with sensitivity ranging between 76% and 97% and
specificity between 71% and 95%.12,13
Pharmacodynamic/Response
Definition: a biomarker used to show that a biological response has occurred in an individual who has been exposed to a medical
product or an environmental agent.
Example in SLE: circulating B-lymphocytes are used as a pharmacodynamic/response biomarker when assessing response to a B-
lymphocyte stimulator-specific inhibitor (e.g., Belimumab) in SLE patients.14
Predictive
Definition: a biomarker used to identify individuals who are more likely than similar individuals without the biomarker to experience
a favorable or unfavorable effect from exposure to a medical product or an environmental agent.
Example in SLE: thiopurine methyltransferase genotype or activity may be used as a predictive biomarker when assessing patients
treated with azathioprine, to identify those at risk for severe toxicity because of high concentrations.15
Prognostic
Definition: a biomarker used to identify the likelihood of a clinical event, disease recurrence or progression in patients who have the
disease or medical condition of interest.
Example in SLE: tubulo-interstitial expression and high urinary levels of TGF-b are predictive markers of chronic renal
damage in LN.16
Safety
Definition: a biomarker measured before or after exposure to a medical product or an environmental agent to indicate the
likelihood, presence, or extent of toxicity as an adverse effect.
Example in SLE: neutrophil count may be used as a safety biomarker when evaluating patients on cyclophosphamide therapy to
adjust dose, or to determine the need to interrupt therapy.17
Susceptibility/Risk
Definition: a biomarker that indicates the potential for developing a disease or medical condition in an individual who does not
currently have clinically apparent disease or the medical condition.
Examples in SLE: HLA-DR3 (HLA-DRB1*0301) allele is strongly associated with SLE susceptibility.18A complete deficiency in one
of the early components of the classical complement pathway genes C1Q, C1R/C1S, C2, C4A, or C4B confers a strong genetic risk
for SLE.19

products (CB-CAPs): erythrocyte-bound complement
activation product C4d (EC4d), erythrocyte-bound
complement receptor 1 (E-CR1), lymphocyte-bounds
complement activation products (TC4d and BC4d)
and platelet bound-C4d (PC4d) and anti-nucleosome
antibodies].26 In addition, they may not be widely
available or their cost may be prohibitive.
Diagnostic biomarkers frequently used in
clinical practice
Anti-dsDNA antibodies
These antibodies are a diagnostic marker and are
included in the ACR, the SLICC, and the 2019
EULAR/ACR classification criteria for SLE.20–22
They are found in up to 70% of SLE patients during
the course of their disease and have 96% specificity for
SLE.21,25,27 They develop early in the course of SLE,
and may even predate its diagnosis,23 particularly in
patients with lupus nephritis (LN).28 Their low diag-
nostic sensitivity (52-70%)21,25,29 is due to their tran-
sient appearance, the laboratory assays used for
identifying them and the isotypes measured. The most
commonly assays for anti-dsDNA detection are
enzyme-linked immunosorbent assay (ELISA) and
immunofluorescence using Crithidia luciliae as sub-
strate. Other used laboratory technique is the Farr
radioimmunoassay (RIA), but most laboratories have
discontinued this assay due to the use of radiolabeled
reagents.
The Crithidia luciliae assay detects antibodies that
bind to the dsDNA in the kinetoplast of this organism.
It detects immunoglobulin (Ig) G anti-dsDNA, IgM
4 Lupus 0(0)
anti-dsDNA, or all isotypes of anti-dsDNA. This test is
relatively specific for anti-dsDNA antibodies because
the kinetoplast contains solely dsDNA. The Farr assay
has the best correlation with disease activity and the
highest specificity for lupus. The Farr assay detects
high-avidity antibodies quantitatively, whereas
ELISA detects both high- and low-affinity IgM
dsDNA antibodies making it less specific than the
other assays.29 When compared, the ELISA assay is
more sensitive but less specific than both the Farr
and the Crithidia luciliae assays.29,30 Another impor-
tant point is that IgG anti-dsDNA seems to be more
specific for the diagnosis of SLE while IgM anti-
dsDNA is less specific and may also be found in
patients with rheumatoid arthritis (RA), Sjogren’s syn-
drome (SjS), and autoimmune hepatitis.29
Anti-Smith (Anti-Sm) antibodies
These antibodies, also included in the SLE classifica-
tion criteria,20–22 are a highly specific diagnostic bio-
marker for SLE with specificity of 99%, but with low
sensitivity being detectable in only 5-30% of SLE
patients.11,21,25,31 Anti-Sm antibodies are virtually
pathognomonic for SLE as they have not been
described in other rheumatic diseases and are hardly
found in healthy individuals. In fact, when detected
in asymptomatic individuals, the onset of SLE usually
follows within a year.23 In clinical practice, because of
its high diagnostic specificity for SLE, clinicians should
consider the diagnosis of SLE even in those individuals
with incomplete lupus erythematosus with positive
anti-Sm antibodies.31
Anti-ribosomal P protein antibodies (anti-P)
These antibodies are also a highly specific biomarker
for the diagnosis of SLE with a specificity between
95%-and 100%.32–35 Anti-P antibodies have been asso-
ciated with neuropsychiatric (NP) SLE (particularly
depression and psychosis), lupus hepatitis, and
LN.32,36 Because of its high specificity for SLE diagno-
sis, some authors have proposed that these autoanti-
bodies should be included in any SLE classification
criteria.32,34,35 The prevalence of anti-P antibodies in
SLE ranges from 10 to 47%, being higher in Asians
and lower in Caucasian and African American
patients.32–34 This variability in the prevalence is due
to the immunoassay used, the ethnic distribution of the
patients studied, the cohorts studied and the patients’
age at disease onset.32 In fact, the positivity of anti-P
antibodies is associated with a younger mean age
among SLE patients being more prevalent in juvenile-
onset SLE (26.7–42%) than in adult-onset SLE
(6.5%–7.7%).33,37,38
Complement proteins C3 and C4
The diagnostic value of complement levels for SLE has
infrequently been examined. Hypocomplementemia
(defined by low serum levels of C3, C4, or total hemo-
lytic complement) was included as an immunologic cri-
terion in the SLICC SLE classification criteria with a
sensitivity of 59% and specificity of 92.6% in the der-
ivation sample.21 The 2019 EULAR/ACR classifica-
tion criteria for SLE also include low levels of serum
complement (C3 and/or C4) as one of the immunolog-
ical criteria with higher weight for both, low C3 and C4
levels than low levels of C3 or C4 alone.22 Accordingly,
Li et al demonstrated that low levels of both C3 and C4
had better diagnostic performance than isolated levels
of C3 and C4 in their Chinese SLE patients.39
Furthermore, they also showed that low C3 or C4
levels with ANA positivity were 94.3% specific for
SLE diagnosis while simultaneous low C3 and C4
levels in association with positive ANA was 97.6%
specific for SLE diagnosis.39 However, their reliability
as diagnostic biomarkers can be limited in some
patients because C3 and C4 are acute-phase reactants
and during inflammation, their synthesis increases,
compensating or balancing their consumption during
complement activation.26
Sensitivities, specificities and predictive values of
these diagnostic biomarkers used in clinical practice
are shown in Table 2.
SLE diagnostic biomarkers not currently
used in clinical practice
CB-CAPs
The importance of CB-CAPs as biomarkers for the
diagnosis of SLE has been demonstrated during the
last two decades.40–52 CB-CAPs are complement split
products bound covalently to blood cells and include
C4d bound to erythrocytes (EC4d), reticulocytes
(RC4d), platelets (PC4d) and B and T cells (BC4d
and TC4d, respectively). CB-CAPs can be measured
by quantitative flow cytometry.40,41
Because C3 and C4 have limited usefulness as lupus
biomarkers, CB-CAPs have been studied as potential
biomarkers for the diagnosis of SLE. Some of the lim-
itations related to the measurement of complement
proteins and soluble split products include: (1) C3
and C4 are substrates rather than products of comple-
ment activation; (2) these complement proteins are also
acute-phase reactants and their increased synthesis
during inflammation can mask their consumption; (3)
the wide range of serum concentrations of C3 and C4
can make it difficult to detect small changes in their
levels during consumption and may not lead to values
González et al.
Table 2. Sensitivity, specificity and predictive value of SLE diagnostic biomarkers used in clinical practice.
Diagnostic biomarker Author (reference)
ANA Petri M, et al. (21)
Amezcua-Guerra, et al. (25)
Anti-dsDNA Petri M, et al. (21)
Amezcua-Guerra, et al. (25)
Kavanaugh AF, et al. (29)
Anti-Sm Petri M, et al. (21)
Amezcua-Guerra, et al. (25)
Anti-ribosomal P protein Mahler M, et al. (34)
Low C3 and/or low C4 Petri M, et al. (21)
Amezcua-Guerra, et al. (25)
ANA: anti-nuclear antibodies; anti-dsDNA: anti double-stranded DNA.
below the normal range; (4) the C4 genetic variability
limits its use as a lupus biomarker as partial deficiencies
of C4 are common among SLE patients, resulting in
persistently low serum C4 levels, which may not be
distinguished from low C4 levels associated with com-
plement activation during increased disease activi-
ty.40,41 Considering these limitations, it was proposed
that CAPs could be more useful than C3 and C4 in
diagnosing, monitoring, and predicting flares in SLE
patients. However, soluble forms of CAPs (e.g. C4d,
C3d, and C3a) are unstable and have short half-lives,
which also limits their clinical use.53–55 In contrast, CB-
CAPs are stable and their half-lives are significantly
longer than those of the soluble forms of CAPs,
making them suitable as lupus biomarkers.40,41 For
example, C3d and C4d bind covalently to blood cell
surfaces and remain attached for the lifespan of the
cell, this stability allows the reliable measurement of
EC4d and BC4d in a clinical laboratory for up to
two days after phlebotomy, in contrast to soluble
CAPs.40,55
Assessment of CB-CAPs in SLE patients has dem-
onstrated that CB-CAPs are sensitive and specific bio-
markers for diagnosis and monitoring SLE with higher
sensitivity than standard complement measurements.46
Early CB-CAPs investigations were performed at the
University of Pittsburg and initially focused on EC4d.
Patients with SLE have higher levels of EC4d than do
patients with other diseases or healthy individuals.42
Manzi et al. demonstrated that increased levels of
EC4d and decreased levels of complement receptor 1
on erythrocytes (E-CR1) are characteristic of SLE, and
combined measurement of these two molecules is a
highly sensitive and specific biomarker for SLE diag-
nosis.42 Other CB-CAPs have also been examined.
PC4d may also be a useful biomarker of SLE, as it is
98 to 100% specific for the diagnosis of SLE compared
5
Positive Negative
predictive predictive
Sensitivity (%) Specificity (%) value (%) value (%)
96.5–99.0 44–45.2 63.9 97.8
57.1–63.0 95.9–97.4 95.5 72.4
26.1–38.0 98.7–100 100 61.7
21.3 99.3 95.6 62.2
59.0–60.0 92.6–99.0 98.4 71.2
with healthy controls and with patients with other dis-
eases, respectively, although it has a low sensitivity
(18%). Moreover, PC4d was significantly associated
with positivity for antiphospholipid antibodies (aPL),
making it a useful marker to identify a subset of
patients at high thrombotic risk.43 Lymphocyte-
bound CAP (LB-CAP) may also serve as biomarkers
for the diagnosis of SLE. TC4d and BC4d have high
diagnostic sensitivity and specificity for SLE. TC4d
and BC4d, respectively, were 56% sensitive/80% spe-
cific and 60% sensitive/82% specific in differentiating
SLE from other autoimmune or inflammatory diseases
diseases.44 Moreover, the TC4d and BC4d assays were
more sensitive for diagnosis of SLE than the anti-
dsDNA, serum C3, or serum C4 when used alone
during a single clinic visit.44 A Swedish study also dem-
onstrated that SLE patients have increased C1q, C3d
and C4d deposition on platelets. They found that
serum of lupus patients with venous thrombosis or a
history of antiphospholipid syndrome (APS) had
increased C4d deposition on platelets as compared to
patients without those manifestations suggesting the
usefulness of PC4d as a marker for venous thrombosis
in SLE. In this study PC4d was found in 48% of SLE
patients and was 96% specific in differentiating SLE
versus healthy individuals.45
The CB-CAPs used for the diagnosis of SLE has
been validated in multicenter studies.46,47 Kalunian
et al., in the CAPITAL (Complement Activation
Products In The Assessment of Lupus) multicenter val-
idation study, demonstrated that a biomarker multia-
nalyte assay panel (MAP) combining anti-dsDNA,
ANA, anti-mutated citrullinated vimentin antibody
(anti-MCV), and EC4d and BC4d was sensitive and
specific for the diagnosis of SLE. The combination of
anti-dsDNA and a positive index score (combining the
weighted sum of ANA, EC4d, and BC4d together with
6 Lupus 0(0)
anti-MCV of >0) was 80% sensitive and 87% specific
for SLE diagnosis against other rheumatic diseases.
Among anti-dsDNA negative SLE patients, the addi-
tion of EC4d and BC4d markers significantly increased
sensitivity while maintaining a high specificity.46 In
another multicenter validation study, Putterman et al.
showed that elevated EC4d and BC4d have a higher
sensitivity than reduced C3/C4 and anti-dsDNA for
SLE diagnosis. In addition, MAP/CB-CAPs that
includes the combination of EC4d and BC4d with
ANA, anti-dsDNA, anti-Sm and autoantibodies asso-
ciated with autoimmune diseases other than SLE (anti-
Jo-1, anti-Scl-70, anti-SS-B/La, anti-centromere B, and
anti-mutated citrullinated vimentin) to produce a two-
tiered index value was 80% sensitive for SLE and 86%
specific versus other rheumatic autoimmune diseases
when a positive test result was present (>0 index
value combining tiers 1 and 2).47
Wallace et al., also validated CB-CAPs for the diag-
nosis of SLE and demonstrated that an elevated expres-
sion of EC4d or BC4d was 43% sensitive and 96%
specific for SLE. The CB-CAPs (EC4d and BC4d) as
components of a MAP algorithm differentiate SLE
from primary fibromyalgia with 100% specificity.48
The utility of MAP/CB-CAPs laboratory testing to
assist rheumatologists in diagnosing SLE in clinical
practice was suggested in two control studies, one ret-
rospective and the other prospective.49,50 The results of
the retrospective study showed an excellent perfor-
mance of this test for SLE diagnosis with a sensitivity
of 83.3%, a specificity of 86.4%, a positive predictive
value of 87% and a negative predictive value of
82.6%.49 The prospective study also showed the clinical
usefulness of MAP/CB-CAPs testing in helping SLE
diagnosis in patients referred to the rheumatologist
for a suspicion of SLE but with low to moderate like-
lihood of SLE.50
Recently, Ramsey-Goldman et al. demonstrated the
usefulness of CB-CAPs as a predictor of the evolution of
probable SLE into SLE as classified by the ACR crite-
ria. CB-CAPs alone or within the MAP algorithm (sen-
sitivities of 28% and 40%, respectively), performed
better as a potential test to support the diagnosis of
SLE in patients with probably SLE than anti-ds DNA
antibodies or low serum complement levels (Sensitivities
of 11% and 9%, respectively). In addition, a MAP score
of >0.8 was the best predictor for a transition to definite
SLE according to ACR criteria.51
The role of CB-CAPs for diagnosis and monitoring
of pediatric-onset SLE (pSLE) was also demonstrated
in a prospective cohort study. Elevated CB-CAPs
(EC4d and BC4d) were 78% sensitive and 86% specific
for a diagnosis of pSLE as compared to patients with
juvenile idiopathic arthritis (JIA) and had higher
sensitivity and specificity than low complement in
pSLE diagnosis.52
Overall, all these studies have demonstrated that
positive CB-CAPs measured directly and within the
MAP algorithm are more sensitive biomarkers than
low serum complement levels or anti-dsDNA biomark-
er in SLE diagnosis. Sensitivities and specificities of
CB-CAPs alone or in the MAP algorithm have been
reported in different studies and vary according to the
cut-off values established and the populations studied.
These data are presented in Table 3.42–52
Anti-nucleosome antibodies
This family of autoantibodies are directed against histone
epitopes exposed in chromatin, against dsDNA and
against conformational epitopes produced by the interac-
tion between dsDNA and core histones.56 The presence
of anti-nucleosome antibodies may be useful, together
with clinical findings and other laboratory tests, in diag-
nosing SLE and drug-induced lupus.57 They have a high
prevalence in SLE, varying from 50% to 100%, and are
considered a more sensitive biomarker of SLE than anti-
dsDNA antibodies; however, these antibodies can be
found in other autoimmune rheumatic diseases such as
mixed connective tissue disease (25%), systemic sclerosis
(SSc)(15%), SjS (7%) or RA (7%).56,57
Data from a systematic review and a meta-analysis
demonstrated that anti-nucleosome antibodies are a
highly accurate diagnostic biomarker for SLE with
good overall sensitivity (61%) and high specificity
(94%); this meta-analysis also showed that anti-
nucleosome antibodies have equal specificity (94%) but
higher sensitivity (60% vs. 52%) and prognostic value
than anti-dsDNA antibodies in the diagnosis of SLE as
the probability of having SLE in an individual with pos-
itive anti-nucleosome antibodies is 41 times greater than
in an individual with negative anti-nucleosome antibod-
ies, while for anti-dsDNA this probability was 28 times
greater.56 Anti-nucleosome antibodies are also a useful
marker for anti-dsDNA negative SLE, being positive in
up to 60% of SLE patients lacking anti-dsDNA antibod-
ies.57,58 In addition, these antibodies can also be a sensi-
tive biomarker for renal involvement in patients with
anti-dsDNA negative SLE.58 Like anti-dsDNA, anti-
nucleosome antibodies are also predominantly associated
with disease flares and LN.57
Despite these promising data, anti-nucleosome anti-
bodies are only sporadically used in clinical practice.
This may be due to the fact that testing for anti-
dsDNA antibodies have been available many years
before and are included in the classification criteria
for SLE and because its diagnostic performance is
still being debated and is not well known.56,59
Furthermore, due to the diversity of anti-nucleosome
González et al. 7

Table 3. Sensitivity, specificity of cell bound complement activation products (CB-CAPs) alone or within MAP algorithms as bio-
markers for SLE diagnosis in different studies.

CB-CAPs Author, year (reference) Sensitivity (%) Specificity (%) vs. comparison group

EC4d/ECR1 Manzi et al, 2004 (42) 81 91 Healthy controls

72 79 Other rheumatic
(inflammatory/ autoimmune)
or hematologic diseases
EC4d Kalunian et al, 2012 (46) 70 93 Healthy controls
83 Other rheumatic diseases
Putterman et al, 2014 (47) 46 99 Healthy controls
88–95 Other rheumatic diseases
Wallace et al, 2016 (48) 24 96 Primary fibromyalgia
Hui-Yuen et al, 2018 (52) - 57 86 Juvenile idiopathic arthritis
Pediatric-onset SLE-
PC4d Navratil et al, 2006 (43) 18 100 Healthy controls
98 Other rheumatic
(inflammatory/ autoimmune),
or hematologic diseases
Kalunian et al, 2012 (46) 46 99 Healthy controls
93 Other rheumatic diseases
Lood et al, 2012 (45) 48 96 Healthy controls
TC4d Liu et al, 2009 (44) 56 80 Other rheumatic
(autoimmune or inflammatory)
diseases
BC4d Liu et al, 2009 (44) 60 82 Other rheumatic
(autoimmune or inflammatory)
diseases
Kalunian et al, 2012 (46) 66 96 Healthy controls
87 Other rheumatic diseases
Putterman et al, 2014 (47) 53 99 Healthy controls
90–96 Other rheumatic diseases
Wallace et al, 2016 (48) 33 100 Primary fibromyalgia
Hui-Yuen et al, 2018 (52) - 63 95 Juvenile idiopathic arthritis
Pediatric-onset SLE-
EC4d and/or BC4d Ramsey-Goldman 61(SLE) 86 Other rheumatic diseases
et al, 2020 (51) 28(probable SLE)
90 Primary Sj€
ogren’s syndrome
84 Rheumatoid arthritis
MAP/CB-CAPs Putterman et al, 2014 (47) 80 86 Other rheumatic diseases
Wallace et al, 2016 (48) 60 100 Primary fibromyalgia
Mossell et al, 2016 (49) 83.3 86 Patients with negative
MAP/CB-CAPs test
(retrospective review
of medical charts)
Ramsey-Goldman 77 (SLE) 96 Other rheumatic diseases
et al, 2020 (51) 44 (probable SLE)
CB-CAPs: cell bound complement activation products; EC4d: erythrocyte-bound C4d; ECR1: erythrocyte-complement receptor 1; PC4d: platelet-
bound C4d; TC4d: T cell-bound C4d; BC4d: B cell-bound C4d; MAP/CB-CAPs (multianalyte assay panel with CB-CAPs): combination of EC4d and
BC4d with eight autoantibodies [ANA, anti-Sm, anti-dsDNA, anti-mutated citrullinated vimentin (anti-MCV), anti-centromere extractable nuclear
antigen (CENP), anti-Jo1, anti-Sc70 and anti-SSB antibodies].

antibodies reactivities, it is necessary to standardize the
nomenclature and the performance of the assays. For
these reasons, some authors consider that the practice
of testing for these antibodies for the diagnosis and
evaluation of disease severity is, at the present time,
questionable.59
Biomarkers for SLE disease activity
Since SLE clinical presentation is characterized by an
unpredictable and fluctuating course with flares and
remissions, assessment of disease activity may be even
more difficult than its diagnosis. Therefore, biomarkers
8 Lupus 0(0)
for a precise assessment of disease activity and prompt
identification of those patients at risk of flare and
organ damage are necessary due to different reasons:
(1) the composite indices used in disease activity assess-
ment [e.g., SLE Disease Activity Index (SLEDAI),60
Systemic Lupus Activity Measure (SLAM)61 or the
British Isles Lupus Assessment Group (BILAG)
index62] are complex as they include a variety of clinical
and laboratory parameters, and are also difficult to
implement in clinical practice because their use requires
appropriate training to interpret and complete them
accurately; (2) distinguishing lupus flares from infec-
tion is oftentimes challenging and optimal treatment
to induce remission is delayed; (3) determining whether
a flare has actually subsided is important in order not
to expose the patients to the potential risk of toxic side
effects of immunosuppressive therapy and, thus, pre-
vent organ damage.
Frequently, the clinical evaluation of disease activity
includes monitoring anti-dsDNA antibodies and serum
complement proteins C3 and C4. Further, other mole-
cules that are not currently used in clinical practice or
are still under evaluation as biomarkers for monitoring
disease activity include anti-C1q antibodies, CB-
CAPs (RC4d, EC4d and EC3d), IFN-a and
IFN-inducible genes, B-cell-activating factor (BAFF)
or B-lymphocyte stimulator (BlyS), a proliferation-
inducing ligand (APRIL), and other candidate moni-
toring biomarkers.4,9,41,63
Anti-dsDNA antibodies
The value of anti-dsDNA antibodies as a marker for
disease activity monitoring has been reported in a vari-
ety of studies that have demonstrated their association
with disease activity,64–67 their predictive value for the
development of LN,68–72 LN flare,70,73,74 SLE flare,75–
77
and new or worsening proteinuria.73 Anti-dsDNA
levels are also impacted by immunosuppressive treat-
ment.78–80 However, their low sensitivity and perfor-
mance limit their value as an independent
biomarker.47 Anti-DNA antibody levels can fluctuate
widely over time in SLE patients.81 Moreover, the
expression of anti-dsDNA antibodies does not always
correlate with active LN, causing uncertainty about its
role as a marker. For example, some patients with LN
lack anti-dsDNA antibodies while other patients with
anti-dsDNA antibodies do not develop LN.81,82 There
are different reasons explaining these discrepancies: (1)
the antibodies that cause LN are deposited in the renal
tissue and cannot be detected in the blood; (2) most
assays for anti-dsDNA antibodies are validated for
diagnosis rather than for disease activity81; (3) non-
nephritic flares, in particular, are not always accompa-
nied by increased levels of anti- dsDNA antibodies83;
(4) not all anti-dsDNA antibodies are pathogenic,
being those of high avidity, of IgG isotype, and
complement-fixing IgG subclass best associated with
disease activity and renal disease.81,82 In fact, high
levels of IgG compared to IgM anti-dsDNA antibodies
have been associated with more active SLE.67
Complement proteins C3 and C4
Autoantibodies lead to immune complexes formation,
which activate and consume complement.84 Thus,
sequential measurements of C3 and C4 or total hemo-
lytic complement CH50 are used in the routine moni-
toring of disease activity. Decreases in C3 and C4 levels
can precede a clinically evident flare and correlate with
disease activity,75 mainly in renal or hematologic
flares.85 However, despite the previously discussed
drawbacks that limit the usefulness of C3 and C4 as
biomarkers of disease activity, especially if used in iso-
lation, these markers are widely used in clinical
practice.
Anti-C1q antibodies
Genetic deficiencies in the early components of the
classical complement pathway are associated with
SLE. About 90% of individuals with genetic C1q defi-
ciency develop SLE and 30% glomerulonephritis.86
Anti-C1q antibodies lead to a C1q deficient state and
may play a pathogenic role in the development of LN
by decreasing the amount of C1q available for effective
clearance of immune complexes and apoptotic bodies
or by either contributing to the formation of circulating
immune complexes that deposit on the glomerular
basement membrane (GBM) or contributing to local
formation of immune complexes on the GBM.13,87–90
Anti-C1q autoantibodies are found in 28-60% of
SLE patients. However, they can also be detected in
other autoimmune diseases, including hypocomple-
mentemic urticarial vasculitis (100%), SSc (26%), RA
(19%) and SjS (14%) and in apparently healthy indi-
viduals (3-5%).87,88 In SLE, anti-C1q antibodies are
more prevalent in patients with LN (60-65%), especial-
ly in those with active LN (74%-89%), than in those
without LN (14-32%).13,90,91 Anti-C1q titer correlates
with active LN, mainly proliferative LN, with a sensi-
tivity of 44-100% and a specificity of 70-92%,12,90,91
while their absence has a negative predictive value for
development of LN close to 100%.13,92
An increase in anti-C1q antibody titer predicts renal
flares in LN with a sensitivity of 81-97% and specificity
of 71-95%,90,91,93–95 suggesting that monitoring anti-
C1q antibodies and their titers in SLE patients may
serve as a non-invasive biological marker for predicting
renal flares.90,91 As anti-C1q and anti-dsDNA have a
González et al.
similar ability to predict renal flares, their combined
assessment is useful, as the absence of both antibodies
practically excludes a renal flare whereas their simulta-
neous presence is associated with a high risk.87,94,95
Despite these findings, anti-C1q antibodies have not
been included in the classification criteria and clinical
management of SLE due to the lack of standardized
laboratory assays and the unavailability for their mea-
surement in most commercial laboratories.87
Erythrocyte sedimentation rate and C-reactive
protein
The inflammatory response in SLE flares is character-
ized by high erythrocyte sedimentation rate (ESR)
values along with low levels of C-reactive protein
(CRP); however, in a subgroup of SLE patients with
serositis and/or arthritis, both ESR and CRP values
increase proportionally and simultaneously.96
Although ESR is a non-specific marker of inflamma-
tion, it seems to be useful to monitor disease activity
especially in non-infected SLE patients.96–98 ESR levels
>25mm/h have been strongly associated with disease
activity in SLE patients.97,98 On the other hand, CRP is
an acute-phase protein synthesized in the liver that has
also been associated with disease activity and therefore
may also be a useful marker to monitor it.99 Although
SLE patients with active disease have higher baseline
levels of CRP than those in remission, CRP levels are
not always associated with disease activity during
flares.96 However, CRP values >10 mg/L are suggestive
of active disease or flare in non-infected patients,100
while levels >50–60 mg/L are 80–84% specific of infec-
tion occurrence.96 However, distinguishing infections
from lupus flare is frequently a clinical challenge; it
has been found that the ESR/CRP ratio may be
useful to differentiate between flare and infection in
patients with SLE being an ESR/CPR >15 suggestive
for disease flare and a ratio <2 associated with
infections.101
CB-CAPs
CB-CAPs have also been studied as biomarkers for
monitoring SLE activity. The capacity of C4d bound
to reticulocytes (RC4d) as an “instant messenger” of
lupus activity has been demonstrated. Due to the short
lifespan of reticulocytes (24–48 hours), and their imme-
diate exposure to C4d generated from activation of the
complement system, reticulocytes bearing C4d may
reflect the current level of disease activity in a patient
with SLE.102
EC4d and EC3d have also been associated with dis-
ease activity measured with The Safety of Estrogens in
Lupus Erythematosus-National Assessment Trial
9
(SELENA)-SLEDAI and the SLAM.65,103,104 EC4d
and EC3d levels were higher in SLE patients than in
healthy controls and patients with other diseases,103,104
and among SLE patients, their levels were higher in
patients with more active than those with less active
disease.103 In addition, the within-patient and
between-patient variability of EC3d and EC4d levels
supports their usefulness as biomarkers for monitoring
disease activity.103
In patients with active SLE, it has been shown that
levels of EC4d, EC3d, anti-C1q decrease with clinical
improvement of disease activity, assessed by non-
serological-SELENA-SLEDAI and the BILAG-2004
index score, while levels of serum C3 and C4 increase
indicating once again the usefulness of CB-CAPs and
anti-C1q in monitoring lupus activity.105
It has also been reported that in patients with chron-
ically low C3/C4 or normal C3/C4, levels of EC4d are
associated with the clinical SELENA-SLEDAI, sup-
porting the association of EC4d with disease activity
regardless of complement C3/C4 status.65
IFNa and IFN-inducible genes
The association between elevated IFNa levels and sero-
logical activity of SLE was first reported in 1979 by
Hooks et al.106 In the early 2000s, Baechler et al.,
using microarray analysis identified a prominent pat-
tern of up-regulated IFN-inducible genes, the “IFN
signature”, in peripheral blood mononuclear cells
from SLE patients. Furthermore, this IFN gene expres-
sion signature served as a marker for severe SLE [renal,
hematologic and central nervous (CNS) system mani-
festations].107 Then, significant associations of
increased expression of IFN-inducible genes and/or ele-
vated serum levels of IFN-regulated chemokines with
increased disease activity, LN, hypocomplementemia,
positive anti-dsDNA and anti-RNA binding antibodies
in SLE patients were also reported.108–114 In cross-
sectional studies, the IFN gene signature was
associated with disease activity at a single point in
time,107–109,114,115 but failed to reflect changes in dis-
ease activity over time in longitudinal studies con-
ducted in patients from the Toronto Lupus Clinic
and the Hopkins Lupus Cohort, indicating that it has
limited clinical usefulness as a biomarker of acute
changes in disease activity.114–116
This lack of association between the IFN signature
and longitudinal changes in SLE activity may suggest
that the expression of IFN responsive genes is not a
dynamic characteristic of SLE, but rather a relatively
stable one that may reflect an inherent activation state
of the IFN pathway.115 However, Chiche et al in a
prospective study identified both stable and variable
IFN signatures over time in single patients.
10
Having observed this dynamic IFN signature in SLE
patients, they found that the variable component of
IFN signature was not exclusively driven by IFNa
but also by IFNb and IFNc and was correlated with
disease activity, and the presence of cutaneous and
renal flares.117
SLE patients carrying the IFN gene signature in
blood have elevated serum levels of IFN-regulated che-
mokines, such as CXCL11 [Interferon-inducible T-cell
alpha chemoattractant (I-TAC)], CXCL13 [B lympho-
cyte chemoattractant (BLC)], CXCL10 (chemokine
CXC motif ligand 10) or IP-10 (IFNc-inducible
protein-10) and CCL3 [macrophage inflammatory pro-
tein 1-a (MIP-1-a)], which have been associated with
more severe and active disease, particularly LN.110 A
longitudinal study designed to validate IFN-regulated
chemokines IP-10 (CXCL10), CCL2 (monocyte che-
motactic protein I), and CCL19 (macrophage inflam-
matory protein 3b)] as biomarkers of SLE disease
activity, demonstrated that serum levels of these che-
mokines correlated significantly with disease activity at
the current visit, rising at SLE flare and decreasing at
remission, performing better than the currently avail-
able laboratory tests (C3, C4, and anti-dsDNA) in the
assessment of current disease activity. In addition,
increasing serum levels of these chemokines also pre-
dicted a disease flare over the ensuing year.111 In anoth-
er prospective longitudinal study at the Charit
e
University Hospital Berlin, IFNa and its response pro-
teins IP-10 and sialic acid-binding Ig-like lectin 1
(SIGLEC1) correlated longitudinally with SLE disease
activity. Increasing levels of IP-10 and SIGLEC1 indi-
cated upcoming flares better than traditional bio-
markers of lupus with specificities of
90%, while
increasing SIGLEC1 expression had the highest sensi-
tivity for detecting flares (83%). Decreasing levels of
IFNa, IP-10, SIGLEC1, anti-dsDNA, by ELISA and
Farr assay, indicated upcoming disease remission, with
sensitivities ranging from 62.5 to 75% and specificities
>90%.118 These data suggest that monitoring serum
levels of IFN-regulated chemokines in SLE may
improve the assessment of current disease activity and
predict a future flare, and therefore may be useful in
individualizing treatment for SLE.
BAFF/BlyS and APRIL
These members of the tumor necrosis factor (TNF)
family are crucial B-cell survival factors. Their expres-
sion increases in the presence of type I IFNs, IFNc, IL-
10 and granulocyte colony-stimulating factor as well as
by the activation of Toll-like receptor (TLR) 4 or
TLR9.119 In SLE patients, increased serum levels of
BAFF/BlyS and APRIL has been reported in 20-67%
and 38-53%, respectively.120 The role of serum BAFF
Lupus 0(0)
or APRIL as biomarkers in SLE is discussed since
some studies have reported correlations between
serum BAFF and APRIL levels and overall disease
activity,121–128 whereas others have not found such cor-
relations.120,128–131 Petri et al. found an association
between BAFF/BlyS concentrations and current and
future disease activity.121 and also demonstrated that
baseline elevated BAFF levels (
2 ng/ml) predicted
moderate-to-severe SLE flare over one year in patients
treated with standard therapy (prednisone with antima-
larials and immunosuppressive agents such as metho-
trexate, mycophenolate mofetil or azathioprine).75
Another study demonstrated that serum BAFF levels
were significantly higher during disease flares than
during remission following B cell depletion therapy in
SLE.128 In contrast, in the phase III Belimumab clinical
trials, no correlation was found between baseline BlyS
levels and the SLE Responder Index (SRI), a compos-
ite measurement of disease activity and response in
SLE.78 The discrepancies observed between these stud-
ies may be due to differences in the study populations,
study design, or disease activity instruments used. In
addition, urinary excretion of cytokines may reduce
serum concentration of BAFF and APRIL in patients
with renal disease.132
Other biomarkers for monitoring lupus disease
activity
Other potential biomarkers for lupus disease activity
include other cytokines [interleukin (IL)-6, IL-10, IL-
12, IL-23, IL-17, IL-18 and TNFa], soluble cytokine
receptors (TNFR, sIL-2 receptor), endothelial activa-
tion markers [sVCAM-1 (soluble vascular cell adhesion
molecule-1), thrombomodulin, circulating endothelial
cells), soluble cell surface molecules (CD27, CD154)
and cellular markers (CD27high plasma cells).4,9,63
Serum levels of IL-6, IL-10, IL-12, IL-23, IL-17,
TNFa and its soluble receptor, have been associated
with disease activity with higher levels in pre-flare
SLE patients compared with non-flare SLE patients.
Thus, they may prove useful biomarkers for lupus
monitoring; they can also play an important role in
drug discovery for lupus treatment.4,63 Elevated
serum levels of VCAM-1 help to discriminate between
active and nonactive SLE, whereas elevated thrombo-
modulin concentrations have been associated with dis-
ease activity and the occurrence of severe
manifestations such as nephritis, vasculitis and neuro-
logical involvement of the central nervous system.7 On
the other hand, in SLE patients, the frequency and
absolute number of CD27high plasma cells is remark-
ably increased in patients with active disease.
Therefore, such alterations of this cell subpopulation
may be important biomarkers for monitoring lupus
González et al.
disease activity.7 Despite these findings, these bio-
markers are not used in clinical practice and multicen-
ter and longitudinal studies are needed to successfully
validate them.
Organ-specific lupus biomarkers
Since SLE can affect multiple organs and not all organs
are affected simultaneously and in the same manner in
all patients, biomarkers that could determine, monitor,
and/or predict organ-specific involvement in an indi-
vidual patient might help identify the best therapy for
that patient, making precision medicine possible in the
treatment of lupus patients. In this, section we will
focus on biomarkers for LN and neuropsychiatric
SLE (NPSLE).
Biomarkers in lupus nephritis
Renal biopsy remains the gold standard for the diag-
nosis, classification and prognosis of LN, and for pro-
viding information that guides the treatment; however,
it is an invasive procedure with potential complica-
tions, it may not reflect the entire pathological status
of the kidneys and it does not predict which patients
will respond to immunosuppressive therapy. In addi-
tion, serial biopsies are impractical in the monitoring of
LN due to their invasiveness and potential unaccept-
able complications.133,134
Traditional laboratory markers for LN such as pro-
teinuria, creatinine clearance, urine protein-to-
creatinine ratio, urine sediment, complement levels,
and anti-dsDNA antibodies are insufficient measure-
ments because they lack sensitivity and specificity for
differentiating active renal disease from irreversible
renal damage. Because they lack the ability to detect
early sub-clinical disease, renal damage may occur
before impaired renal function is detectable by these
laboratory tests. Furthermore, persistent proteinuria
can be due to chronic lesions instead of ongoing
inflammation and renal flares can occur without an
evident increase in the degree of proteinuria.5 Other
biomarkers for diagnosing and monitoring renal
involvement in lupus, include anti-C1q and anti-
nucleosome antibodies; their role and drawbacks for
monitoring LN were previously discussed in this
review. Thus, more sensitive and specific biomarkers
that are able to discriminate active inflammation
from irreversible renal damage, predict renal flares,
monitor response to treatment and disease progression
are certainly required.
Urinary biomarkers seem to be more promising than
serum biomarkers, as they arise directly from the
inflamed tissue and reflect the pathological changes in
inflamed kidneys in real-time.135 Because urine is an
11
easily and non-invasively obtainable biological
sample, it becomes an important fluid to examine.135
However, important considerations must be taken into
account: (1) diurnal variations in urinary molecules
concentrations can occur; (2) urinary infections
should be ruled out as they also affect urinary bio-
markers measurement; (3) because most inflammatory
diseases share common molecular pathways, it is pos-
sible that a potential biomarker may not be specific for
a particular disease, although it may be useful for pre-
dicting and/or monitoring the inflammatory process.135
Over the past decade, multiple serum and urinary
biomarkers have been studied for monitoring LN.
Here we will present the main biomarkers grouped by
their biological characteristics.
Cytokines. Elevated urinary levels of pro-inflammatory
cytokines, IL-6 and IL-17, have been found in active
and severe forms of LN [World Health Organization
(WHO) class III/IV].136,137 These studies suggest that
urinary levels of IL-6 may be valuable for monitoring
progression of LN as they decrease after treatment136
whereas urinary IL-17 levels are valuable as a diagnos-
tic biomarker for LN.137 On the other hand, in patients
with LN a significant positive correlation between IL-6
and IL-17 serum concentrations during periods of
activity as well as during remission has been reported,
suggesting their usefulness as predictors for response to
treatment and remission of LN.138 However, the asso-
ciations of both serum and urinary IL-6 and IL-17 with
LN require further validation.135 Urinary and serum
IL-10 levels have also been found significantly higher
in patients with LN compared to SLE patients without
LN.135
Urinary levels of TNF-like weak inducer of apopto-
sis (uTWEAK), another proinflammatory cytokine,
have been found to be significantly higher in SLE
patients with active renal disease and in those under-
going a renal flare than in lupus patients with non-
active renal disease and chronic stable disease.
Moreover, uTWEAK levels also correlate with renal
SLEDAI scores and predict LN.139,140 These studies
report the value of using uTWEAK as a biomarker
for monitoring LN and for predicting renal
flares.139,140 However, both serum and urine levels of
TWEAK are not specific for LN, as they may be ele-
vated in patients with active renal involvement in anti-
neutrophil cytoplasmic antibodies (ANCA)-associated
vasculitis.141
Adiponectin is an adipocyte-derived cytokine with
pro- and anti-inflammatory effects. It induces produc-
tion of monocyte chemoattractant protein-1 (MCP-1),
a pro-inflammatory chemokine.142 Urine adiponectin
levels are significantly increased during renal flares,
but not with non-renal SLE flares and correlate with
12
proteinuria and serum creatinine; furthermore, urine
adiponectin levels increase significantly within two
months of renal flare and decline to preflare levels
within four months of treatment. Plasma adiponectin
levels are also increased in patients with renal SLE flare
compared to patients with non-renal SLE flare, but in
contrast to urine levels, plasma adiponectin does not
change significantly before, during, or after renal flare.
These data suggest that urine adiponectin may be a
fairly sensitive marker of renal SLE flare.143
Chemokines. Urinary levels of the pro-inflammatory
chemokine MCP-1 (uMCP-1) are significantly higher
in patients with active LN, especially in patients with
proliferative disease, compared to those with inactive
LN, SLE patients without renal involvement and con-
trol subjects and also correlate with renal lupus disease
activity.144–149 In longitudinal studies uMCP-1 levels
are increased two to four months before renal
flares,146 and decrease during clinical remission in
response to immunosuppressive therapy,146,148 whereas
in non-responders, uMCP-1 levels remain persistently
high.146 The results of a recent meta-analysis indicate
that uMCP-1 has high diagnostic value in active LN
with sensitivity and specificity of 89% and 63%,
respectively.149 Overall, uMCP-1 levels may serve as a
biomarker for predicting impending renal flares, and
serial uMCP-1 measurements are a useful tool for mon-
itoring response to immunosuppressive treatment. In
addition, uMCP-1 is a biomarker with high diagnostic
value for active LN.146,149
Urinary levels of IP-10 (uIP-10 or uCXCL10),
another pro-inflammatory chemokine, have been
found to be significantly increased in active SLE
patients compared with inactive patients or healthy
individuals,148 and correlate with renal activity,
SLEDAI score and 24-hours proteinuria.150 The mea-
surement of urinary mRNA levels of IP-10 and its
receptor CXCR3 are useful in diagnosing class IV
LN as their levels are increased in this class but not
in others.16
On longitudinal follow-up of active renal patients,
urinary IP-10 levels decreased significantly in respond-
er patients after treatment,16,148 whereas levels tended
to increase in non-responders.16 These findings indicate
that urinary IP-10 is a useful biomarker of renal activ-
ity, and serial monitoring of its urinary levels can pre-
dict response to treatment.16,148,150
Urinary levels of other inflammatory chemokines
such as CXCL ligand 16 (CXCL16) and mRNA
expression of RANTES (Regulated on Activation,
Normal T cell Expressed and Secreted) have been
found to be elevated in patients with active LN.151,152
Elevated urine CXCL16 levels have been found to be
associated with SLEDAI scores and proteinuria.151
Lupus 0(0)
In juvenile SLE, elevated serum levels of soluble
CXCL16 have been correlated positively with
SLEDAI score, 24-hours proteinuria, and severity of
LN according to histological findings of the renal
biopsy.153 On the other hand, increased urinary levels
of RANTES are predictors of renal flare in patients
with diffuse proliferative LN.152
Adhesion molecules. VCAM-1, an adhesion receptor of
the endothelial cell member of the immunoglobulin
superfamily, is over-expressed by both infiltrating leu-
kocytes and resident renal cells in the presence of pro-
liferative LN.154 Urinary levels of soluble VCAM-1 are
significantly higher in patients with SLE and active LN
compared to SLE patients without LN and healthy
controls,155,156 and correlate significantly with disease
activity, damage (SLICC/ACR Damage Index, SDI),
low C3 level, decreased creatinine clearance, and more
severe LN (classes III, IV, and V).155–158 Overall,
VCAM-1 appears as a promising biomarker for LN
activity and severity. However, urinary VCAM-1 is
not specific for LN, as high levels are also present in
other inflammatory nephropathies (e.g., ANCA-
associated glomerulonephritis, focal segmental glomer-
ulosclerosis and membranous nephropathy).158
Nevertheless, longitudinal studies will be required to
validate its effectiveness as potential biomarker for
LN. On the other hand, a meta-analysis reported that
SLE patients have elevated urinary and serum levels of
intracellular adhesion molecule-1 (ICAM-1) compared
to healthy controls, but serum ICAM-1 did not differ-
entiate active and inactive SLE.159
Growth and fibrosis factors. Transforming growth factor-b
(TGF-b) is a potent inducer of vascular endothelial
growth factor (VEGF) expression that induces vascular
permeability leading to proteinuria and participates in
interstitial matrix remodeling.135 In patients with class
IV LN, urinary TGF-b and VEGF mRNA levels are
significantly higher than those found in patients with
class II, III, and V but comparable to those in class VI
LN (diffuse glomerulosclerosis). Such upregulation of
TGF-b and VEGF in class IV and VI LN indicates
tissue repair and fibrosis.16 A significant reduction in
urinary TGF-b and VEGF mRNA levels has been
observed in LN patients who went into remission
after treatment, while in non-responder patients uri-
nary TGF-b and VEGF mRNA tended to increase.16
These findings suggest that TGF-b may be a potential
marker of predicting chronicity in LN.
Other urinary biomarkers. Neutrophil gelatinase-
associated lipocalin (NGAL) or lipocalin-2 is a glyco-
protein that belongs to the lipocalin family. It is
expressed in neutrophils, kidney, liver and epithelial
González et al. 13

cells in response to various pathologic states, such as
inflammation, infection, ischemia, acute kidney injury
and malignancy.160 Urinary NGAL (uNGAL) is pro-
duced by injured nephron epithelia160 and has been
recognized as one of the most promising biomarkers
of renal involvement in SLE. It is a sensitive biomarker
for discriminating SLE patients with or without
LN137,144,161 and among patients with LN for distin-
guishing those with active from inactive LN.144
Furthermore, uNGAL levels strongly correlate with
renal disease activity (renal SLEDAI-2k), renal
damage (renal domain of the SDI), and activity and
chronicity indices on renal biopsy but not with extra-
renal disease activity or extrarenal damage.137,162,163
Recently, a meta-analysis assessed the diagnostic per-
formance of uNGAL in LN. The results showed that
uNGAL was a useful biomarker for diagnosis (sensi-
tivity of 84% and specificity of 91%), estimation of
activity (sensitivity of 72% and specificity of 71%)
and prediction of renal flare (sensitivity of 80% and
specificity of 67%) of LN.164
Other urinary biomarkers that have been found to
be correlated with active LN include osteoprotegerin,
kidney injury molecule-1 (Kim-1), high-mobility group
box 1 proteins (HMGB1þ), BAFF, and APRIL among
others.134,135,165,166 The different urinary biomarkers
are summarized in Table 4.
Biomarkers in neuropsychiatric SLE
Autoantibodies, that get into the CNS, pro-
inflammatory cytokines and/or chemokines play a
role in ischemic and inflammatory mechanisms that
contribute to the development of different neuropsychi-
atric SLE (NPSLE) manifestations and have been pro-
posed as laboratory NPSLE biomarkers. However, a
significant percentage of CNS manifestations are not
directly attributable to SLE, but to the side effects of
medications, infections, primary neuropsychiatric (NP)
diseases, among other non-SLE etiologies.167,168
Alongside the laboratory biomarkers, different
neuroimaging techniques such as magnetic resonance
imaging (MRI) and nuclear medicine imaging have
allowed the characterization of neurological structural
or functional abnormalities. Although these laboratory
and neuroimaging biomarkers are used in clinical prac-
tice to attribute NP manifestations to SLE, none of
them are specific enough as an NP-SLE biomarker.168
Therefore, there is a need for diagnostic biomarkers
that help clinicians to differentiate NPSLE from NP
events from other etiologies as well as biomarkers
that correlate closely with disease activity and are valu-
able in the management of NPSLE.
Potential laboratory biomarkers associated with
NPSLE are obtained from blood draws or from the
cerebrospinal fluid (CSF).169 aPL antibodies [lupus
anticoagulant (LAC), anticardiolipin and anti-b2GP1
antibodies) are not only serological biomarkers, but
also contributors to the development of thrombotic
events and other NPSLE manifestations, and have
been used as diagnostic biomarkers of NPSLE and
for treatment decisions.169 aPL antibodies in serum
and/or CSF are associated with focal NP manifesta-
tions (cerebrovascular disease, seizures, chorea) and
with diffuse NP manifestations (cognitive dysfunction,
psychosis, depression and headache).170,171
Anti-P antibodies, as discussed previously in this
review, are particularly associated with episodes of psy-
chosis and severe depression in SLE.32,36 However,
they are not valuable in differentiating among various
neuropsychiatric phenotypes and measurements in
CSF may be more accurate for diagnosis than measure-
ment in serum.169,172
Anti-glutamate-receptor antibodies are a subset of
anti-dsDNA antibodies that cross-react with NMDA
(N-methyl-D-aspartate) receptors which are widely dis-
tributed throughout the brain, with high density in the
amygdala and hippocampus, regions implicated in
emotional processes and memory.169 The presence of
antibodies against NMDA receptor (anti-NMDAR) in
CSF is associated with diffuse CNS manifestations of
NPSLE (acute confusional state, anxiety disorder,

Table 4. Urinary biomarkers in lupus nephritis according to their biological characteristics.

Cytokines Chemokines Adhesion molecules Growth and fibrosis factors Other urinary biomarkers

IL-6 MCP-1 VCAM-1 TGF-b NGAL (lipocalin-2)

IL-17 IP-10 (CXCL10) ICAM-1 VEGF Osteoprotegerin
IL-10 CXCR3 Kim-1
TWEAK CXCL16 HMGB1þ
Adiponectin RANTES BAFF/APRIL
Interleukin (IL); TWEAK: TNF-like weak inducer of apoptosis; MCP-1: monocyte chemoattractant protein-1; IP-10: IFNc-inducible protein-10; CXCR3:
CXC chemokine receptor type 3;CXCL16: CXC chemokine ligand 16; RANTES: Regulated on Activation, Normal T cell Expressed and Secreted;
VCAM-1: Vascular cell adhesion molecule-1; ICAM-1: intracellular adhesion molecule-1; TGF-b: transforming growth factor-b; VEGF: vascular
endothelial growth factor; NGAL: Neutrophil gelatinase-associated lipocalin (NGAL); kim-1: kidney injury molecule-1; HMGB1þ: high-mobility group
box 1 proteins; BAFF: B-cell-activating factor (BAFF); APRIL: a proliferation-inducing ligand.
14
cognitive dysfunction, mood disorder and psychosis)
and may differentiate patients with central NPSLE
from patients with peripheral NPSLE.173,174
In a meta-analysis a higher positivity of serum anti-
NMDAR was found in patients with NPSLE com-
pared to SLE patients without NPSLE; however, dis-
tinguishing specific NPSLE syndromes could not be
achieved.175
Overall, NPSLE patients are more likely to have
elevated serum levels of aPL, anti-P and anti-
neuronal antibodies compared with SLE patients with-
out NP involvement and a significant increased
prevalence of positive titers for CSF anti-neuronal anti-
bodies as compared to SLE patients without NP
manifestations.171
Cytokines and chemokines also have a role as diag-
nostic biomarkers in NPSLE. Increased CSF levels of a
variety of pro-inflammatory cytokines (IL-6, IL-10,
IFNa, IFNc and TNFa) and chemokines (IL-8,
MCP-1, RANTES, and IP-10) have been associated
with NPSLE.169 Among these, IL-6 has been shown
to have the strongest positive association with
NPSLE,176 and the presence of IL-6 and IL-8 is one
of the most common traits described in the CSF of
patients during the clinical activity of NPSLE.169,176
Thus, the CFS levels of IL-6 and IL-8, might represent
a biomarker for the diagnosis of NPSLE.176 In patients
with NPSLE, serum BAFF levels are found to be ele-
vated whereas serum APRIL levels are found to be
reduced.120
In SLE patients, CSF levels of APRIL were shown
to be 24-fold higher than those of healthy controls, and
levels of BAFF 200-fold higher, suggesting high intra-
thecal levels of APRIL and BAFF as a feature of SLE.
Moreover, APRIL levels, but not BAFF levels, were
higher in the CSF of NPSLE patients compared with
those without CNS disease.177
The identification and validation of specific NPSLE
biomarkers in peripheral blood and CSF is required as
they may be valuable in the treatment of NPSLE.
Among all these NPSLE biomarkers, only LAC has a
place as a clinically useful biomarker as its positivity
may classify the NP involvement and therefore help in
the therapeutic decision-making process.168
Neuroimaging biomarkers
Both anatomical and functional neuroimaging techni-
ques are used for identifying CNS abnormalities.
Computer tomography (CT), magnetic resonance
imaging (MRI), magnetization transfer imaging
(MTI), diffusion tensor imaging (DTI), or diffusion-
weighted imaging (DWI) are used for assessing
structural imaging of the brain while functional MRI,
positron emission tomography (PET), single-photon
Lupus 0(0)
emission CT (SPECT), magnetic resonance spectrosco-
py (MRS), or magnetic resonance angiography (MRA)
can be utilized for evaluating functional brain imag-
ing.169 MRI is the imagen technique of choice for
NPSLE, although in 40-50% of the patients no abnor-
malities are detected. The most common finding is sub-
cortical and periventricular white-matter
hyperintensities, frequently in the frontal-parietal
regions. However, these lesions are not specific as
they are also may be present in patients without NP
manifestations.178 Based on their availability, advanced
MRI techniques (MRS, MTI, DTI, DWI, PET or
SPECT) are recommended when conventional MRI is
normal or does not provide an explanation for CNS
manifestations.178,179 These studies may detect addi-
tional white matter and grey matter abnormalities as
they are more sensitive to subtle neuronal injury and
demyelination; however, as these lesions are nonspe-
cific for NPSLE these studies may not differentiate
NPSLE from other etiologies of NP disease.178
Multi-omics approaches in lupus research
Research in SLE has been done at several levels,
including DNA (genomics), epigenetic (epigenomics),
mRNA (transcriptomics), protein (proteomics) and
metabolites (metabolomics). These methods are used
in order to find potential markers in SLE, these poten-
tial biomarkers are depicted in Supplementary Table 1.
In the case of DNA, GWAS (genome-wide associa-
tion studies) and NGS (next generation sequencing) are
used to identify gene loci or SNPs (single nucleotide
polymorphisms) associated with SLE. But also, epige-
netic modification can be used as biomarkers. The
three main types of epigenetic modifications are
DNA methylation, histone modifications and
microRNA (miRNA).180
Genes associated to SLE included several pathways,
like nuclear factor kappa-light-chain-enhancer of acti-
vated B cells (NFjB) signaling, TLR and type I IFN
signaling, DNA degradation, apoptosis and clearance
of cellular debris, immune complex processing and
phagocytosis, neutrophil and monocyte function and
signaling, and T-cell and B-cell function and signal-
ing.181 More than 80 SLE susceptibility loci have
been identified.182 Furthermore, genetic variation can
affect disease susceptibility modifying genetic expres-
sion levels [expression quantitative trait loci
(eQTLs)].182 This approach combined genotype and
gene expression data leading to a better explanation
of the true impact of SNPs.
However, the heterogeneity of symptoms in patients
with similar genetic load suggests there are other fac-
tors impacting on the expression of the genes. Some of
these factors are evaluated with epigenetics. DNA
González et al.
methylation could be analyzed in specific cells (like T
cells or B cells) or in total blood.183–189 In fact, meth-
ylation has been reported as an early event in disease
flares,190 suggesting epigenetic modifications could be a
potential biomarker in SLE. Among them, for exam-
ple, the methylation level of IF144L promoter differ-
entiates patients with SLE from healthy individuals
and other autoimmune diseases like RA or primary
SjS.191 miRNAs are small, evolutionarily conserved
noncoding RNA derived from much larger primary
transcripts encoded by their host genes. miRNAs
bind complementary sequences of their targets
mRNAs and negatively regulate protein expression.192
Some of them (miR-126 and miR-146a) have been
associated with disease activity.181 Histone modifica-
tions included acetylation, methylation, ubiquitination,
phosphorylation and sumoylation. In general, acetyla-
tion promotes gene expression and methylation reduces
gene expression. Evidence of histone modifications in
SLE is less solid than the other epigenetic evidence.193
Transcriptomics is the study of the mRNA, it
means, the gene expression.181 In SLE, there is a tran-
scriptional signature relate to type I interferon, and this
signature has been associated with a higher disease
activity116; however other groups have not found this
association.194 This signature has been used to monitor
response in clinical trials.195,196 Transcriptomics have
been examined in several cells like neutrophils, B-
cells, T-cells, hematopoietic stem and progenitor
cells.197–200
Proteomics evaluates the products of the translation
from RNA to proteins, it should be done by mass
spectrometry-based technologies and multiplex high-
through-put protein arrays. These techniques allow
biomarker identification and drug target discovery.
As proteins are final products, we can identify proteins
involved in the pathogenesis of SLE (potential drug
targets) or consequence of a dysfunctional immune
system (potential biomarkers).201 More than 200 pro-
teins have been identified as potential biomarkers,
some of them for SLE patients in general, but others
for specific organs involved like LN or NPSLE.202–204
Metabolomics is the study of small molecules (less
than 1kD) including endogenous metabolites like car-
bohydrates, amino acids, oligopeptides, organic acids,
nucleotides or lipids and exogenous molecules (xeno-
biotics) such as drugs, food, toxins, among others.205
Metabolomic studies are carried out mainly with three
methods, liquid chromatography-mass spectrometry,
gas chromatography-mass spectrometry and the third
one is MRS.206 These techniques could identify pat-
terns associated with cardiovascular disease, neuropsy-
chiatric and renal involvement.207–209
15
Conclusions
Although a high number of novel biomarkers have
been studied for diagnosis, monitoring of disease activ-
ity and response to treatment in SLE patients, few have
been validated through large-scale longitudinal studies
and none of them has been standardized for their use in
clinical practice. Thus far, there is no a single lupus
biomarker that meets the characteristics of the ideal
biomarker. In contrast, the combination of currently
available biomarkers along with clinical evaluation is
often necessary for a better diagnosis and monitoring
of disease activity. Therefore, there is a need to identify
better biomarkers and for this, novel omics techniques
are being developed for the identification of novel bio-
markers which may help identifying susceptible indi-
viduals in early stages of the disease, assist in the
assessment of disease activity, in selecting better thera-
peutic regimens, and in evaluating response to therapy.
Likewise, research on the discovery and validation of
new markers in biological samples (serum, urine, or
CSF) continues for a better understanding of lupus.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iDs
Luis Alonso González https://orcid.org/0000-0002-6523-
3919
Manuel Francisco Ugarte-Gil https://orcid.org/0000-
0003-1728-1999
Graciela S Alarc

on https://orcid.org/0000-0001-5190-9175
Supplemental material
Supplemental material for this article is available online.
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