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SPECIAL ARTICLE
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
10.1177/0961203316644338
806
Table 1
Autoantibody test
Sensitivity estimate
(based on
refs 26, 23)
Specificity
for SLE?
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
Other diseases
Many
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.
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807
Aim
Information
base
Sensitivity
Specificity
Diagnosis
Classification
808
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.
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809
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.
Lupus
810
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).
Funding
The author(s) received no nancial support for the
research, authorship, and/or publication of this
article.
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