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Lupus (2016) 25, 805811

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SPECIAL ARTICLE

Toward new criteria for systemic lupus


erythematosusa standpoint
M Aringer1, T Dorner2, N Leuchten1 and SR Johnson3
1

Department of Medicine III, University Medical Center and Faculty of Medicine Carl Gustav Carus at the TU Dresden, Dresden, Germany;
2
Department of Medicine, Rheumatology and Clinical Immunology, Charite Universitatsmedizin Berlin & DRFZ Berlin, Berlin, Germany; and
3
Division of Rheumatology, Department of Medicine, Toronto Western Hospital, Mount Sinai Hospital; Institute of Health Policy, Management
and Evaluation, University of Toronto, Toronto, Canada

While clearly different in their aims and means, classification and diagnosis both try to accurately label the disease patients are suffering from. For systemic lupus erythematosus (SLE),
this is complicated by the multi-organ nature of the disease and by our incomplete understanding of its pathophysiology. Hallmarks of SLE are the presence of antinuclear antibodies
(ANA), and multiple immune-mediated organ symptoms that are largely independent. In an
attempt to overcome limitations of the current sets of SLE classification criteria, a new fourphase approach is being developed, which is jointly supported by the European League
Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). This
review attempts to delineate the performance of the current sets of criteria, the reasons for the
decision for classification, and not diagnostic, criteria, and to provide a background of the
current approach taken. Lupus (2016) 25, 805811.
Key words: Systemic lupus erythematosus; classification criteria; ANA; autoantibodies;
immune complexes

Introduction
Dening systemic lupus erythematosus (SLE), both
in classication and in clinical diagnosis, has
remained one of the challenging questions in
Rheumatology. After all, the very nature of this
condition is not fully understood. SLE will often
be the underlying condition when patients present
with either a combination of fever, lymphadenopathy, malar rash and polyserositis, or with immune
complex glomerulonephritis, but may also present
as new-onset polyarthritis or another organ-specic
manifestation with no other obvious symptoms.
Therefore, some experts view SLE as a syndrome
rather than a single disease. Dividing SLE into separate entities in such a way, however, might mean
assigning specic phenotypes to very small groups
of patients, or even to single patients. Abolishing
the common idea of one disease would help neither
our understanding of the pathophysiology of the
Correspondence to: Martin Aringer, MD Rheumatology, Medicine III
University Medical Center TU Dresden, Fetscherstrasse 74, 01307
Dresden, Germany.
Email: Martin.aringer@uniklinikum-dresden.de

disease, nor clinical decision making today. In our


view, there are sucient similarities to keep the
faces of SLE together, and we favor the standpoint
of seeing SLE as one disease.
It is of course evident that SLE can have literally
hundreds of manifestations related to autoimmunity, which possibly are independent of each other.
In addition to cellular immune activation, it is the
hallmark of the disease that these manifestations
are due to various antibodies and often to
immune complexes consisting of autoantigen and
autoantibodies. In fact, essentially all inammatory
manifestations of SLE are associated with immune
complexes, while cytopenias and some nervous
system symptoms are probably initiated by the
direct eects of autoantibody binding.1,2 For
many organ manifestations, the autoantibody specicities at fault are not fully known. However, in
the worldwide routine setting, there are still more
than a dozen autoantibodies3 that are being measured and are associated with SLE at dierent
degrees of sensitivity and specicity (Table 1).
Most of the autoantibodies measured in clinical
practice for SLE assessment are directed against
nuclear antigens. The complete absence of

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10.1177/0961203316644338

SLE Classification Criteria


M Aringer et al.

806

Table 1

Autoantibodies in SLE diagnosis and classification.

Autoantibody test

Sensitivity estimate
(based on
refs 26, 23)

Specificity
for SLE?

ANA (HEp-2 IFLU)


Anti-dsDNA
Anti-Histone
Anti-C1q
Anti-Sm
Anti-Ro60

98
50
50
30
10
40

No
Yes (95%)
No
No
Yes (99%)
No

Anti-SSB/La
Anti-U1RNP
Rheumatoid factors
Anti-Cardiolipin IgG
Anti-Cardiolipin IgM
Lupus anticoagulant

20
20
20
20
10
10

No
No
No
Noa
Noa
Noa

mechanisms that underlie this dangerous main feature of the disease.

Other diseases
Many

DIL, SSc, JIA


IC vasculitidesa

Sjogrens,
CLEa, SSc
Sjogrens
MCTD
RA, Sjogrens
Primary APSa
Primary APSa
Primary APSa

a
The differential diagnoses can also be part of the SLE spectrum.
IFLU: immunofluorescence; DIL: drug-induced lupus; SSc: systemic
sclerosis; JIA: juvenile idiopathic arthritis; IC: immune complex; CLE:
cutaneous lupus erythematosus; MCTD: mixed connective tissue disease; RA: rheumatoid arthritis; APS: anti-phospholipid (Hughes)
syndrome.

antinuclear antibodies (ANA) is, in fact, a rather


uncommon situation in patients whom most SLE
experts would nd to have SLE,46 and roughly
half of all SLE patients have antibodies to
double-stranded DNA (dsDNA), at least in episodes of disease activity.7 Antibodies to dsDNA,
but also those to RNA, achieve binding to the
nuclear acids via dierences in charge. This important biophysical characteristic, presumably in an
indirect way via histone binding,8 also explains
their anity to basal membranes. It appears somewhat uncertain whether the propensity to form
such antibodies truly is an inherent feature of the
disease, or whether the immune system is simply
more prone to developing such antibodies based
on the MHC association than autoantibodies to
other antigens.
Even more than the propensity to develop
ANA, the development of multiple autoantibodies
is the cardinal feature of SLE.9,10 In fact, it appears
that the development of SLE is associated not only
with the new occurrence of autoantibodies typical
of SLE, but also with the development of antibodies associated with organ-specic autoimmunity,
such as autoimmune thyroiditis.9,10 The distinction
between organ-specic and systemic autoimmunity
is still underexplored and imprecise. Since we
commonly limit testing to well-dened autoantibodies, the known antibody ndings only constitute
a part of the whole picture. Many other
autoantibodies may be present. It is still unclear
whether there are common or numerous distinct

SLE classificationthe ACR and


the SLICC criteria
To a signicant degree, both the 1982 (and
revised 1997) American College of Rheumatology
(ACR) and the 2012 Systemic Lupus International
Cooperating Clinics (SLICC) sets of classication
criteria depict the above-sketched picture of the
prototypical multi-organ systemic autoimmune disease.4,5,11 These criteria mostly list organ manifestations that are likely antibody and/or immune
complex mediated in this setting.
Being among the rst sets of criteria derived with
modern technology, the 1982 (and revised 1997)
ACR criteria have shaped the concept of SLE of
most of the physicians practicing today. In fact,
most physicians will have learned them by heart.
This very fact, however, also represents a point
of criticism. One of the reasons for learning the
criteria by heart was that they are not entirely intuitive. Nevertheless, they have worked well for clinical and various other studies, and have often even
been (inadequately) used for diagnostic purposes.
Over time, new features of SLE have been
described, such as subacute cutaneous LE, and it
has been debated whether all of the cutaneous and
mucocutaneous featuressuch as UV sensitivity,
oral ulcers and skin lesionsare indeed independent, or represent manifestations of the same SLE
manifestation.12 While specicity was usually considered satisfactory, the sensitivity of the ACR criteria has been seen as suboptimal, in new-onset and
childhood SLE in particular.13 Moreover, the 1997
revision was never formally tested. The latter has
changed through a substantial eort by the SLICC
group to devise new SLE criteria. In this process
the SLICC investigators also validated the 1997
criteria, and found a sensitivity of 83% and a specicity of 96%.5 The SLICC group have made a
number of a priori choices that have shaped their
set of criteria. Primarily, they decided that the
structure of the criteria should stay the same. In
consequence, four features are still needed for
SLE classication, and the features have not been
weighted. However, there is one important exception: biopsy-proven lupus nephritis was declared to
suciently classify the disease when in combination
with ANA or anti-dsDNA antibodies. The SLICC
investigators also chose to better depict the role of
autoimmunity. This resulted in the denition that

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classication demands at least one immunological


and at least one clinical criterion being fullled.
While both the decisions on biopsy-proven lupus
nephritis and on the necessity to have at least one
immunological criterion make intuitive sense, it is a
fact that these were more eminence based than data
driven. The other choice that was not entirely based
on data is the inclusion of a full textbook list of all
possible forms of acute, subacute, and chronic cutaneous LE, which were subsequently tested together
under these combined headings. Accordingly, there
are no data on the performance of rather unusual
entities such as lupus tumidus, which is also rarely
associated with SLE.1416 Similarly, the list of
neuropsychiatric symptoms was expanded, and
some of the other denitions were slightly modied.
The SLICC group dened improved sensitivity
as a major goal, and their SLE criteria have
indeed clearly surpassed the 1997 ACR criteria
in this regard. Several groups have compared
the two sets, and there is complete agreement
that the SLICC criteria are more sensitive.13,1720
The SLICC criteria sensitivity has been found in
the range between 92% and 97%, whereas the
1997 ACR criteria had 77% to 91% sensitivity.
However, and not entirely unexpectedly given the
similar structure, specicity dropped from 9196%
for the 1997 ACR criteria to 7488% for the
SLICC criteria. It is therefore not clear which set
of criteria is more useful, and there is some resulting uncertainty and local dierence in the preferred
set. Having only one set would, in the longer term,
be clearly preferable, but for trial purposes either of
the two is acceptable to the Food and Drug
Administration and European Medicines Agency
regulatory agencies.

Differences between diagnosis and classification


As compared with classication by criteria, clinical
diagnosis is actually quite dierent. Diagnosis and
classication both aim at accurately deciding
whether the underlying disease in an individual
patient is or is not SLE. However, the purposes
dier, and so do the means (Table 2).21 While classication mainly denes a rather homogenous set
of patients for research purposes, diagnosis focuses
on the individual patients prognosis and therapy.
In consequence, suboptimal sensitivity in diagnosis
can be a very serious problem. With 95% sensitivity, 1 in 20 true SLE patients would still be missed
and not given appropriate treatment. This is one of
the most relevant arguments against diagnostic

Table 2 Differences between diagnosis and classification.

Aim
Information
base
Sensitivity

Specificity

Diagnosis

Classification

Individual prognosis and


therapy.
Theoretically unlimited
information of various
natures and sources.
Critical issue (will often
limit access to therapy).

Homogenous groups for


research purposes.
Feasible, and therefore
limited set of objective
criteria only.
Low sensitivity narrows
patient population, but
is usually not critical.
Critical issue (starting
point classification
cannot be corrected).

Diagnosis will be questioned if new information sheds doubt.

criteria. Not meeting the diagnostic criteria would


endanger these patients, if in need of expensive
therapies in particular. This is one of the major
arguments why neither ACR nor EULAR are willing to back diagnostic criteria.21 Low specicity
may also have an impact on health care cost, in
part caused by additional testing.22 However, the
diagnosis of SLE in itself, without any proof of
relevant organ disease, should therapeutically lead
to the use of hydroxychloroquine (and perhaps
vitamin D) only. Basing more therapeutic steps
on the SLE diagnosis would be a signicant
misconception.
On the other hand, criteria will only be useful if
practicable. Optimally, they are easily learned by
heart, or printed on one single page. In contrast,
in making a diagnosis the conventional way, the
treating physician will be able to take any piece of
information into account. A family history of autoimmunity, or rather unspecic features such as
arthralgias, myalgias, or fatigue, may tip the balance towards the diagnosis. Additional information, such as old laboratory reports that showed
leukocytopenia long before disease onset, may
lead to discounting certain features. It is important
in this regard that diagnosis is seen as an ongoing
and reiterative process. Physicians should re-question their diagnosis whenever the course of disease
does not t expectations.
The latter would have dramatic consequences in
classication. A patient fullling classication criteria for SLE, who would accordingly be included
into a randomized therapeutic trial, cannot be
simply withdrawn by post hoc change of classication. Specicity thus is a critical issue in classication. In contrast, for classication purposes, 90%
sensitivity would allow for inclusion of most
patients, and the 10% missed will usually not
make a dramatic dierence. Therefore, fundamentally dierent from diagnosis, sensitivity is not so
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critical in classication. These dierences are also


shown in Table 2.

SLE diagnosis
It is, therefore, evident why neither the ACR nor
the SLICC classication criteria for SLE should be
directly used for diagnostic purposes. Even the best
sensitivity and specicity values of these sets show
that at least 4% of patients would incorrectly be
given, or not given, the diagnosis. Nevertheless,
these criteria shape our understanding of SLE.
They provide a framework to model our diagnostic
process on; this process will eventually go much
further. What is it, then, that will indicate a diagnosis of SLE? Looking at the two sets of criteria,
they mainly depict multiple autoimmune features
that together form the disease. Some of these features are quite specic, such as immune complex
glomerulonephritis or autoantibodies to the Smith
(Sm) antigen.4,5 Others may be relatively specic
given the right test and/or the right circumstances,
such as anti-dsDNA antibodies or pleuritis in the
absence of infection and pulmonary embolism. Still
others, including positive ANA or arthritis, are in
fact quite unspecic.5,23
Under these circumstances, dierential diagnoses
are an important aspect of the diagnostic work-up.
These include infections (viral infections, in particular), hematological disease, and a wide variety of
autoimmune diseases. The latter include entities
clearly distinct from SLE, such as Hashimotos thyroiditis, rheumatoid arthritis or primary Sjogrens
syndrome, but also such that can occur both as entities on their own or as part of the SLE spectrum, for
example anti-phospholipid syndrome, autoimmune
hemolytic anemia, or cutaneous LE.
The challenge is to screen the patients symptoms
and results for those SLE-compatible symptoms
most probably induced by immune complexes, or
by specic autoantibodies (IgG type). Complement
consumption, usually measured as decreased C3c
and/or C4, is evidence for immune complex disease.
Two or more independent antibody-mediated or
immune complex-mediated features that are compatible with SLE will usually make the diagnosis
likely. However, there are situations that make a
rm diagnosis dicult. A prominent example is
bacterial endocarditis, which often leads to
immune complex disease,24 and may be accompanied by various immune phenomena.
If there is clinical suspicion of SLE, ANA usually
is a good screening test with high sensitivity.

Nevertheless, if there is substantial evidence for


the disease, testing for anti-dsDNA antibodies
and antibodies to extractable nuclear antigens
(ENA) is recommended in addition.25,26 This is
mainly based on ndings that anti-Ro60 and certain other SLE-related autoantibodies may be
missed by ANA testing using HEp-2 cells.27 In
our opinion, ANA (or ENA or anti-dsDNA antibodies) plus at least two independent SLE organ
symptoms not otherwise explained, or one such
symptom and an independent antibody, usually
make the diagnosis quite likely. For example, arthritis in the absence of anti-CCP antibodies, but with
positive ANA and positive anti-dsDNA antibodies
(detected by a specic test) will be diagnosed as
SLE, unless there is an acute infection known to
often elicit autoantibodies. It is interesting that a
similar approach was independently used in
Sweden.19 It is obvious that more specic symptoms will be given more weight in the diagnostic
process. Anti-dsDNA antibodies in the absence of
ANA should be regarded with great caution, since
this situation means that one result must be clinically wrong. Nevertheless, and without any fault on
the part of the laboratory, such situations occasionally occur.
In most instances, this is a fairly straightforward
approach, but it may, for example, be challenging to
decide between infection plus SLE and infection
alone. There are two important caveats. In our opinion, nobody should receive a diagnosis of SLE if
there are no disease symptoms. Autoantibody combinations may eventually be found to predict future
disease,28,29 and this might then invite early therapeutic measures in the future, but there is no disease
without symptoms. The other aspect is that a diagnosis of SLE in itself calls for hydroxychloroquine,
and probably vitamin D and sun protection, but
neither necessitates glucocorticoids or immunosuppressive agents, nor does it impact on who best cares
for an individual patient. In the latter regard, two
dierent, independent LE skin manifestations in the
presence of ANA will usually mean underlying SLE,
but the patient will still be best cared for by a
dermatologist.

A process towards new classification criteria


In full awareness of the dierences between diagnosis and classication of SLE,21 would it not still be
helpful to get closer to the diagnostic process with
classication criteria? A feasible set of classication
criteria will still not make for a diagnostic tool, but

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parallel ways of reasoning for classication and


diagnosis would make life easier. Therefore, we
have embarked on a large SLE criteria project,
which is jointly supported by the EULAR and the
ACR, and accordingly guided by a steering committee of 12 members. The aim is to develop classication criteria with specicity comparable with
the ACR 1997 criteria, but with improved sensitivity, in early disease in particular.30 In addition, we
would like to arrive at a more intuitive approach
that is easier to learn. It is important that the criteria approach rigorously keeps to scientic methods, and that circular reasoning is avoided.3134
In order to achieve this, a four-phase process was
developed. In phase I, publications on ANA sensitivity and specicity were collected in a systematic
literature review.6,35 This was based on the idea
that in a patient with clinical suspicion of SLE,
such as in a young female patient with otherwise
unexplained myalgias and fatigue, the next step in
diagnosis would be to test for ANA. Likewise, for
classication criteria, the performance characteristics of ANA would better t the description of an
entry criterion. HEp2 ANA immunouorescence
data of 10,089 SLE patients was included, and analyzed by meta-regression. At a titer of 1:80, a sensitivity of 98.1% was calculated, with a
corresponding specicity of 83.3%. At 1:160, sensitivity was 95.4%. Accordingly, ANA of at least
1:80 may indeed represent a useful entry criterion.
Additional tests, for example for antibodies against
DSF-70, which almost exclude SLE, could improve
ANA specicity,36 but they are not (yet) available
worldwide. In the remainder of the rst phase, the
focus has been item generation, based on three different approaches. First, a large international
expert Delphi exercise resulted in a list and rating
of criteria that should be considered for SLE classication for adults as well as for children.37 Second,
in an international, multiethnic, adult early SLE
patient cohort, ndings in patients with SLE were
compared with those of patients with mimicking
conditions.38,39 Third, patient members of the
German lupus patient association were approached
via their quarterly magazine Schmetterling
(buttery), and asked to anonymously ll in and
mail a paper survey on symptoms they had around
the onset of their disease. More than 300 patients
responded.40 The inclusion of the patient perspective
has not historically been done in criteria development, and is a novel aspect of this work.
In the second phase, item reduction was done in
a nominal group technique exercise with the steering committee and a group of high-prole SLE
experts from both North America and Europe

who were not members of the steering committee.


The expert panel distinguished potential entry criteria, which would be required for classication,
from other potential additive criteria. Redundant
or poorly performing criteria were removed. An
abstract reporting the results has been submitted to
the 2016 EULAR congress in London. Since there
has been a suggestion that criteria cluster into clinically sensible domains or buckets, it is currently
being evaluated whether single features are independent of each other. This is done both in a literature
review and using the data of the early patient international cohort. With this information, the items will
be weighted in Phase 3, using multicriteria decision
analysis,41,42 as was done for the ACR/EULAR
rheumatoid arthritis and systemic sclerosis classication criteria.4346 Finally, in Phase 4, the newly
derived candidate criteria will be tested in large independent patient cohorts, and against both the 1997
ACR and the 2012 SLICC criteria.

Conclusions
In part because the medicolegal implications of not
meeting diagnostic criteria for SLE in an SLE
patient would convey risks, there is consensus
that diagnostic criteria will not be backed by
either EULAR or ACR. In contrast, classication
criteria not only shape our understanding of the
disease, but also serve as a useful backbone for
the diagnostic approach in an individual patient.
Thus, further improving the classication criteria
appears worthwhile. The challenge to classify a
highly variable disease such as SLE, which is characterized by a tendency to develop multiple autoantibodies, has not changed since the 1982 ACR
criteria. While some clinical advances, including
the denition of additional forms of cutaneous
lupus and several newly described autoantibodies,
have enriched the eld, most of the more common
features were known already in 1982. Given the
high quality of the available sets of criteria, which
slightly dier in sensitivity and specicity, devising
new classication criteria for SLE is a considerable
challenge. In a large, collaborative transatlantic
project, we hope to meet this challenge. At least,
in a scientically rigorous approach, a robust set of
criteria should be formed and validated, all of
which will be based on a strong rationale. The project is intended to be fully inclusive, and everybody
who wants to take part is invited to contact all or
any of the authors. Hopefully, 2017 will bring us
back to uniformly accepted criteria.
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Acknowledgements
The SLE classication criteria project is jointly
supported by the EULAR and the ACR. While
this article represents only the opinion of the
authors, this is based on discussions and work
within the SLE criteria steering committee, and
we owe thanks to our colleagues in this committee
(Dimitrios Boumpas, Karen Costenbader, David
Daikh, David Jayne, Diane Kamen, Marta
Mosca, Josef Smolen, David Wofsy).

Declaration of Conflicting Interests


The author(s) declared no potential conicts of
interest with respect to the research, authorship,
and/or publication of this article.

Funding
The author(s) received no nancial support for the
research, authorship, and/or publication of this
article.

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