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Journal of Autoimmunity xxx (xxxx) xxxx

Contents lists available at ScienceDirect

Journal of Autoimmunity

journal homepage: www.elsevier.com/locate/jautimm

Review article

Inflammatory markers in systemic lupus erythematosus

Martin Aringer
University Medical Center and Faculty of Medicine Carl Gustav Carus at the TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany

ARTICLE INFO ABSTRACT

Keywords: While systemic lupus erythematosus (SLE) is an autoantibody and immune complex disease by nature, most
Systemic lupus erythematosus of its organ manifestations are in fact inflammatory. SLE activity scores thus heavily rely on assessing
C-reactive protein inflammation in the various organs. This focus on clinical items demonstrates that routine laboratory markers of
Anemia
inflammation are still limited in their impact. The erythrocyte sedimentation rate (ESR) is used, but represents
Cytokines a rather crude overall measure. Anemia and diminished serum albumin play a role in estimating inflammatory
Chemokines
activity, but both are reflecting more than one mechanism, and the association with inflammation is complex. C-
reactive protein (CRP) is a better marker for infections than for SLE activity, where there is only a limited
association, and procalcitonin (PCT) is also mainly used for detecting severe bacterial infection. Of the cytokines
directly induced by immune complexes, type I interferons, interleukin-18 (IL-18) and tumor necrosis factor
(TNF) are correlated with inflammatory disease activity. Still, precise and timely measurement is an issue,
which is why they are not currently used for routine purposes. While somewhat more robust in the assays,
IL-18 binding protein (IL-18BP) and soluble TNF-receptor 2 (TNF-R2), which are related to the respective
cytokines, have not yet made it into clinical routine. The same is true for several chemokines that are increased
with activity and relatively easy to measure, but still experimental parameters. In the urine, proteinuria leads
and is essential for assessing kidney involvement, but may also result from damage. Similar to the situation in
serum and plasma, several cytokines and chemokines perform reasonably well in scientific studies, but are not
routine parameters. Cellular elements in the urine are more difficult to assess in the routine laboratory, where sufficient rout
Therefore, the analysis of urinary T cells may have potential for better monitoring renal inflammation.

1.Introduction
Systemic lupus erythematosus is a classical systemic autoimmune
disease. Autoantibodies and immune complexes are so central [1,2] that both
diagnosis and classification serologically focus on these features. Indeed,
neither the new European League Against Rheumatism (EULAR)/American
College of Rheumatology (ACR) 2019 classification criteria [3,4], nor the
Systemic Lupus International Collaborating Clinics (SLICC) 2012 [5], the ACR
1997 [6] or the ACR 1982 classifi-cation criteria [7] for SLE contain any
markers of inflammation. C-re-active protein (CRP), as the prototypical
marker of inflammation in the routine laboratory, is often not greatly elevated
in SLE (see below) and in fact should raise suspicion of bacterial infection if
highly elevated in an SLE patient. Still, the immune complexes in SLE almost
invariably lead to inflammation. Indeed, the majority of the clinical features
are inflammatory (Table 1).
2. Linking immune complexes with inflammation
Accordingly, with exception of the hematological manifestations
and a relevant part of the neuropsychiatric manifestations, SLE organ disease
is inflammatory disease. It is therefore helpful to understand the mechanisms
linking immune complex deposition and inflammation in the various organs.
Where immune complexes form or get deposited depends on their size, their
specificity, and on their charge. While we do not fully understand and cannot
currently measure most of the auto-antibodies probably involved, notable
measurable examples are anti-bodies to double-stranded DNA (dsDNA) in
proliferative lupus ne-phritis, deposited on the charged basement membrane,
and antibodies to the RNA-binding Ro-60 protein in subacute cutaneous LE
(SCLE).
Deposited immune complexes activate the immune system both by
complement activation and by Fc receptor binding. At least in murine models
of the disease, Fc-receptors are essential for renal disease [8].
Cell death is effected by cytotoxic T cells and the complement terminal
membrane attack complex, whereas inflammation is mostly induced by
monocytes/macrophages. Binding immune complexes, monocytes/
macrophages produce a variety of pro-inflammatory cytokines, such as TNF
[9], interleukin-1 (IL-1), IL-6, IL-15 and IL-18. TNF, IL-1, IL-6 and IL-18 are
also found highly overexpressed in the kidneys in murine and/or human lupus
nephritis [10], and thus directly linked to inflammatory

E-mail address: martin.aringer@uniklinikum-dresden.de.

https://doi.org/10.1016/j.jaut.2019.102374
Received 20 November 2019; Accepted 20 November
2019 0896-8411/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Martin Aringer, Journal of Autoimmunity, https://doi.org/10.1016/j.jaut.2019.102374
Machine Translated by Google

M. Aringer Journal of Autoimmunity xxx (xxxx) xxxx

Table 1 Table 2
Inflammatory and non-inflammatory clinical features in the EULAR/ACR 2019 Inflammatory markers and manifestations in validated SLE activity scores. Este
criteria [3]. The clinical criteria items of the EULAR/ACR 2019 SLE criteria are table lists the inflammatory organ manifestations (upper part) and in-inflammatory
listed with their individual weights, denoting inflammatory disease and direct laboratory parameters (lower part) used in validated SLE disease
autoantibody effects. Class III or IV and class II or V nephritis refer to the International activity indices, namely British Isles Lupus Activity Group (BILAG) score,
Society of Nephrology/Renal Pathology Society (ISN/RPS) classifi-cation of lupus European Consensus Lupus Activity Measure (ECLAM), SLE Index Score (SIS),
glomerulonephritis. SLE Disease Activity Index (SLEDAI) and Systemic Lupus Activity Measure
(SLAM). Please note that for most of the score items the inflammatory com-ponent
Domain Criterion Weight Inflammatory
is already visible from the wording used (marked in bold letters).
Renal Class III or IV nephritis Class 10 Forks
BILAG ECLAM SIS SLAM SLEDAI
II or V nephritis Proteinuria 8 Forks

> 0.5 g/day Joint involvement 4 Forks

Clinical
Musculoskeletal Acute pericarditis 6 Forks
Active SLE rash Forks Forks Forks Forks Forks
Serosal Pleural/pericardial 6 Forks
Bullous injuries – – Forks – –
effusion Malar rash Subacute 5 Forks
Forks – Forks Forks Forks
Alopecia
Mucocutaneous cutaneous LE 6 Forks
Mucosal ulcers Forks Forks Forks Forks Forks
4 Forks
Panniculitis Forks – – Forks –
Discoid LE 4 Forks
Vasculitis Forks Forks Forks Forks Forks
Oral ulcers 2 Forks
Forks Forks – Forks Forks
Arthralgias
Alopecia 2 Probably Arthritis Forks Yes Forks Forks Forks

Neuropsychiatric Seizure 5 Partly Forks – Forks Forks –

Myalgia
Psychosis 3 Usually not Forks – Forks Forks –
Myositis
Delirium 2 Partly Pneumonitis Forks Forks Forks Forks –
Hematological Autoimmune hemolysis 4 No ILD Forks Forks Forks Forks –
Thrombocytopenia 4 No Pleuritis Forks Forks Forks Forks Forks

Leukopenia 3 No Pericarditis Forks Forks Forks Forks Forks

Constitutional Unexplained fever 2 Partly Forks – – Forks –
Myocarditis
Aortitis Forks – – – –
Peritonitis Forks Forks Forks Forks –
Forks – – – –
Hepatitis
Forks – – – –
Cholecystitis
BAFF Pancreatitis Forks – – Forks –

D.C. b Seizures
CNS vasculitis
Forks

Forks
Forks

Forks
Forks

Forks
Forks

Forks
Forks
–
– – –

IFN T PlasmaC Myelitis

Inflammatory neuropathy
Forks
– –
Forks
– –
Orbital inflammation Forks – – – –

AAbs Keratitis
Uveitis
Forks

Forks
–
–
–
–
–
–
–
–
C' Laboratory
I.C. Increased ESR – Forks Forks Forks –

Leukocyturia Forks Forks Forks Forks Forks

Hematuria Forks Forks Forks Forks Forks

Urinary casts Forks Forks Forks Forks Forks

Proteinuria Forks Forks Forks Forks Forks

pDC M Renal histology (last 3 months) Yes

– – – –

3. SLE activity is mostly inflammatory activity

IFN IL-6 TNF
IL-6
- Pro-inflammatory cytokines and effector cells of the immune system
+ then lead to inflammatory organ disease. Looking at major validated
CRP
liver
Fig. 1. Connections between immune complex deposition, cytokines and some
of the specific cytokine functions of interest in SLE. AAbs autoantibodies, IC
immune complexes, Cÿ complement, Mÿ monocytes/macrophages, pDC plas-
macytoid dendritic cells, IFNÿ interferon-ÿ, IL-6 interleukin-6, TNF tumor necrosis
factor, BAFF B cell activating factor/B lymphocyte stimulator, CRP C -reactive
protein. B lymphocytes, T lymphocytes, DC (monocyte derived) den-dritic cells.
disease. Besides these inflammatory pathways, the detection of immune
complexes also leads to the production of type I interferons and of cy-
tokines that are immunoregulatory rather than pro-inflammatory, such
as IL-10, IL-15 and B cell activating factor/B lymphocyte stimulator
(BAFF/BLyS) [11–13](Fig. 1).
SLE disease activity scores, such as the British Isles Lupus Activity
Group (BILAG) score, the European Consensus Lupus Activity Measure
(ECLAM), the SLE Index Score (SIS), the SLE Disease Activity Index
(SLEDAI) and the Systemic Lupus Activity Measure (SLAM) [14,15], it
it is apparent that most of the organ activity is actually inflammatory
activity (Table 2). It is rather obvious that most of the organ
manifestations demonstrate inflammation by the ending “-itis” or the adjective
“Inflammatory”, even though some, such as lupus skin rashes or mu-
cosal ulcers are not called dermatitis or mucositis. Most of the organ
symptoms thus are a consequence of immune complex deposition and
the ensuing inflammation. Notable exceptions to this inflammatory
majority phenotype of SLE manifestations are cytopenias (leukopenia,
thrombocytopenia and hemolytic anemia), thrombotic events in sec-
ondary anti-phospholipid syndrome (APS) and some of the
neuropsychiatric manifestations, all of which are directly mediated by
autoantibodies.
Regarding laboratory markers included in the SLE activity scores
(Table 2), complement consumption is a marker of immune complex
deposition, not yet of inflammation, and the ESR is related both to
autoimmunity and to inflammation (see below). Thus, lupus activity as
estimated by the validated instruments combines direct autoantibody

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M. Aringer
effects and measures of autoimmunity and immune complex deposition
with clinical evidence of organ inflammation. Still, so much of SLE
activity is in fact inflammatory that lupus activity by any of these scores
roughly equals inflammatory activity.
4. The erythrocyte sedimentation rate (ESR) and contributors to
an increased ESR
The ESR has long been known to be regularly elevated in active SLE.
It is thus logical that an elevated ESR is included in three out of five
validated SLE activity scores (Table 2). In principle, increases in ESR
can either be due to changes in serum proteins or to changes in erythrocytes.
The former typically include hypergammaglobulinemia,
monoclonal gammopathy and increased fibrinogen levels. The latter
Mostly reflect reduced erythrocyte number and erythrocyte size. some
of these ESR-accelerating factors are inflammatory, others are not. To
understand the inflammatory component in the increased ESR, it is
therefore necessary to look at all of these components.
4.1. Protein components to the increased ESR
While relevant oligoclonal and monoclonal gammopathies occur,
they are by far not the rule in SLE patients, and not directly explained
by SLE. In contrast, polyclonal hypergammaglobulinemia is common in
SLE [16], fitting an autoantibody-mediated disease. Hypergammaglo-bulinemia
is a sign of B cell and plasma cell hyperactivity and thus of
autoimmunity, not of inflammation. While IL-6 is an exception in that it
actually stimulates B cells, most of the pro-inflammatory cytokines ra-ther limit
than expand polyclonal antibody production.
We therefore have to look to other rather abundant proteins with
regard to representing inflammatory disease. Fibrinogen is often elevated with
inflammation as part of the acute phase response. However,
In contrast to other inflammatory disorders, such elevations are usually
only mild in SLE [17]. Moreover, and likewise contrasting with other
conditions, fibrinogen does not appear to be correlated with IL-6 in
lupus inflammation [18]. On the other hand, low fibrinogen may occasionally
occur, as a consequence of intravascular activation of the
coagulation cascade, but this would not increase the ESR. Fibrinogen
therefore is probably not a relevant cause of the increased ESR in active
SLE.
In contrast to fibrinogen, which increases the ESR by being over-produced
in the acute phase response, plasma albumin has the opposite
effect. Sufficient levels tend to keep the ESR lower, while diminished
production of albumin increases the rate. Plasma albumin has been
shown to be clearly decreased in SLE vs healthy individuals and in
active SLE vs inactive disease [19]. Inflammation can directly exert
negative influence on the production of albumin in the liver, as part of
the acute phase response. At the same time, decreased appetite, influenced by
increased TNF levels, for example, may also play a relevant
role. Both mechanisms may be relevant in active SLE. However, kidney
albumin loss via damaged glomeruli (below) probably is the most important
factor in reducing serum albumin, also suggested by the more
apparent association in patients with lupus nephritis [19]. The influence of
reduced albumin on the ESR therefore is a first inflammatory
component.
4.2. Anemia
The other relevant inflammatory component of the ESR is anemia.
Low hemoglobin and erythrocyte levels are a common finding in patients with
active lupus [20]. This is only occasionally due to hemolytic
anemia, which is a typical sign of SLE, carrying 4 points in the new
EULAR/ACR 2019 criteria (Table 1) [3], but has a relatively low pre-valence in
SLE [5]. As mentioned before, hemolytic anemia would also
have to be categorized as a direct autoimmune feature, caused by an-tibodies
to erythrocytes, but not a marker of inflammation.
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Indeed, it is the anemia of chronic disease that is fairly common in
SLE [20]. There usually is a direct link via IL-6, linking to increased
hepcidin [21–23]. Based on serum levels, this link could not be established in
SLE [24], but was also not seen in a larger study in RA [25],
where the effect of this pathway was suggested to be rather clear
[26,27]. At least, an association between increased ferritin, another
acute phase component, and disease activity was shown for SLE [28].
Furthermore, it is conceivable that high interferon levels, as found in active SLE
(see below), lead to anemia [29,30]. All of these may lead to
the association between anemia and SLE disease activity [31].
That low hemoglobin is also predictive of renal flares [24] likely is
due to disease activity, as just discussed. However, renal involvement
may also be reflected by decreased erythropoietin. The later almost
certainly is an independent factor for anemia in SLE patients with renal
damage, and will then be primarily related to damage rather than ac-tivity. In the
often young female patients with SLE, the hypochromic
anemia of iron deficiency would be expected to be very common, and
this has indeed been demonstrated [20]. Iron deficiency has been
clearly shown to reduce hepcidin [25], and this may interfere with its
association with IL-6.
5. Routine serum/plasma markers of inflammation
5.1. C-reactive protein
CRP is the standard marker of inflammation, but in SLE patients,
CRP is more of a marker for severe infections (Table 3). It is therefore of
interest to analyze the role of CRP in SLE in some detail. CRP is directly
driven by IL-6 [32], and IL-6 levels are increased in active SLE [33,34].
Indeed, CRP is often not entirely normal in active SLE [35,36]. Higher
CRP levels are found in patients with active serositis [37], arthritis
[38], or myositis [39]. In most other situations, however, CRP levels
will remain below 60 mg/L or 6 mg/dL in active SLE [35]. Levels higher
than these are much more likely in severe infections. CRP values of
150 mg/L or 15 mg/dL make infections very likely, while 20 mg/L
(2 mg/dL) CRP or less make infection unlikely [39]. This is of clinical
importance given that severe infections are a major cause of death in
SLE patients [40–42].
Of interest, while CRP levels, without infection, are higher in active
SLE than in inactive SLE, the opposite is true in infections in SLE patients [36].
Accordingly, patients with severe infections have a trend
towards lower levels of CRP if they have active SLE than if their SLE is
inactive [36]. One could argue that this was a consequence of im-
munosuppression. This, however, is unlikely given that this phenom-enon is
limited to SLE and perhaps other connective tissue diseases, but
not found in ANCA associated vasculitides or giant cell arteritis.
Therefore, it is much more likely that SLE activity impacts on the
production of CRP. One hypothesis in this regard is an influence of type
I interferons, which appear to reduce IL-6 signaling [43,44], in line with
the fact that a majority of patients with active SLE display an interferon
signature [45,46].
Since the ESR is increased in active SLE, but CRP is usually not to
Table 3
Routine laboratory markers of infection and inflammation. The main routine
laboratory parameters used in assessing SLE disease activity are shown, with
their relative levels in active infection and active lupus inflammatory disease as
well as under the influence of lupus autoimmunity (autoantibody production
and immune complex deposition). *Elevations are more common in serositis,
myositis and arthritis.
parameters Infection Lupus inflammation Lupus autoimmunity
ESR high high elevated (IgG)
–
CRP may be elevated* high
Procalcitonin mildly elevatedhigh –
Complement C3 (C4) Increased (relatively increased) decreased
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M. Aringer
this degree, it is not too surprising that the ratio of ESR over CRP is
much higher in active SLE than in SLE with infection [47]. Vice versa,
the ratio of CRP over ESR is an even better predictor of a severe in-fection
than CRP alone [39].
5.2. Procalcitonin
In contrast to CRP, procalcitonin (PCT) is almost exclusively used as
a marker of severe bacterial infections, such as septicemia or pneumonia
[48]. PCT is not entirely specific and can be increased in some
hematological conditions in the absence of infection. In fact, patients
with active SLE also have increased PCT levels [36], but this increase is
usually only mild, so that levels > 0.5 ng/mL usually signal infection
[49]. Therefore, PCT is not a useful marker for SLE disease activity, but
may provide evidence of a relevant infection above relevantly increased
CRP. PCT may be particularly helpful for the differentiation between
SLE with active pleuritis and infection, since it is not usually increased
in SLE serositis, in contrast with CRP [49].
5.3. Complement proteins
The measurement of components of the complement system is a
well established part of the assessment for disease activity [14]. Indeed,
diminished complement components are so typical for SLE that they
have become part of the SLICC classification criteria [50] and have
retained this role in the new EULAR/ACR classification criteria [3,4] for
SLE. While total (lytic) complement, measured by CH50 (or CH100)
was the first established test, the direct measurement of complement
proteins C3 and C4 is the most commonly used approach today. genetics
deficiencies of upper complement components, such as C1q, C1r, C1s,
or C4, predispose for SLE [2,51]. This is presumably because of di-
minished removal of apoptotic cell bodies in their absence, so that
apoptotic cells, which are not inciting inflammation, look over time
more like other forms of dead cells, and lead to an inflammatory re-action
of the immune system [52,53]. For C1q, recent data also show a
downmodulating effect of C1q on CD8 positive T cells, exerted via their
mitochondrial metabolism [54].
C4 deficiency is not that uncommon in SLE, and C4 measurements
in regular intervals are not useful in these patients. In most SLE patients,
however, both the complement proteins C3 and C4 can be
measured to quantify immune complex disease. The classical pathway
of complement activation starts with immune complexes binding C1q
and the recruitment of C1r and C1s. C4, C2 and C3 are consecutively
split in the process of complement activation, with the larger C4b and
C3b (as well as C2a) components, respectively, remaining with the
active complex, while the smaller C4a and C3a parts, called anaphy-
latoxins (together with C5a), have chemotactic functions.
Most of the current tests measure C3 and C4 whole complement
levels. Since these proteins are split within the complement cascade, the
whole protein levels are decreasing. However, complement proteins are
also part of the acute phase, and this in contrast leads to an increase in
C3 and C4 protein. In infection, it is obviously sensitive to have enough
complement protein available for fighting the pathogen. In con-sequence,
inflammation increases, but immune complex disease de-creases
complement proteins [55], and the levels of C3 and C4 (as well
as CH50) result from both mechanisms. In active SLE, C3 and C4 are
often diminished [56], so that the direct effect of immune complex
induced complement activation, reflecting the autoimmune component,
dominates the inflammatory response component. More novel tests that
detect split products are even more specific for the autoimmune component,
eliminating the acute phase response side. Therefore, while
complement acts on the very border between autoimmunity and in-
flammation, the measurement of complement components is essentially
related to the Immunology side, and the reflection of inflammatory
activity indirect only.
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5.4. S100 proteins
The alarmins of the S100 family are monocyte/macrophage or
neutrophil derived proteins that are recognized by Toll-like receptor 4
(TLR4) [57]. In this way, they clearly trigger inflammatory functions in
immune cells. As markers, the S100 proteins have entered Rheumatology
mostly via autoinflammatory disease in pediatric patients [58].
The most abundant of these, the calcium binding proteins S100A8
and S100A9 were found increased in active SLE as compared to inactive
disease and decreased under immunomodulatory therapy [59–61]. Of
interest, while S100A8/A9 proteins were associated with clinical dis-ease
activity [59] as well as with anti-dsDNA antibodies and active
nephritis, they were negatively correlated with skin disease [60]. Since
type I interferons may play a particularly important role in SLE skin
manifestations [62], one could hypothesize that the S100A8/A9 re-sponse
could be negatively regulated by interferons, similar to the situation with
CRP discussed above. S100A8/A9 were also found in active disease and
then associated with cardiovascular risks [63]. While of
pathophysiological interest, they are probably not a perfect candidate
for an overall marker of inflammatory disease activity.
Another S100 protein, S100A12 may prove more useful in this re-gard.
S100A12 was among those proteins with the highest difference
between SLE patients and healthy individuals [64] and better correlates
with disease activity than S100A8/A9 [65,66]. These data make
S100A12 an interesting potential candidate for SLE inflammatory dis-ease
activity.
6. Cytokines and chemokines
In addition to the above mentioned routine markers, a variety of
cytokines are clearly associated with SLE activity. Among those are the
type I interferons, and IFNÿ in particular, IL-6, IL-10, IL-15, IL-18,
BAFF/BLyS and TNF [12,19,33,46,67–72]. While IFNÿ is mainly made
by plasmacytoid dendritic cells (pDC) [73], the others of these cyto-kines
are mostly derived from monocytes and macrophages. In contrast
to these, T cell cytokines that act more locally, such as IFNÿ, can usually
not be measured in sufficient quantities. Among the cytokines increased
in SLE, IL-10, IL-15 and BAFF/BLyS predominantly play an im-
munoregulatory rather than an inflammatory role (Table 4).
6.1. IFNÿ
The type I interferons, including IFNÿ, but also IFNÿ, IFNÿ, IFNÿ,
IFNÿ, IFNÿ and IFNÿ, are not so easily grouped in that they exert un-ique
functions and combine immunoregulatory and a specific kind of
pro-inflammatory functions [74]. As mentioned above, type I inter-ferons
interfere with the CRP production induced by IL-6 [43], which is
well in line with their central role in virus infections, but not bacterial
infections. However, interferons promote the secretion of proin-inflammatory
cytokines as well as the differentiation and activation of
immune cells and steer the immune system towards activation and
Table 4
Cytokines increased in sera of patients with active SLE. Listed are cytokines
with a positive correlation to (inflammatory) disease activity or a clear pro-
inflammatory role in SLE. The degree of association with disease activity and
the main functional category in SLE are shown.
Cytokine Association with activity Main functional role
IFNÿ good specific interferon effects
IL-6 Modest pro-inflammatory
IL-10 good Immunoregulatory
IL-15 Modest Immunoregulatory
IL-18 good pro-inflammatory
good
BLyS/BAFF Immunoregulatory
TNF good pro-inflammatory
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M. Aringer
often inflammation [74–76]. Type I interferons are notoriously difficult to
measure [77], and ELISA technology often fails to perform adequately.
Starting with type I responding cells [77], peripheral blood mRNA signatures
of type I interferons developed as the main parameter of today, so that we
actually measure the cytokine influence rather than the cytokine today [78].
Type I interferons and their signature are as-associated with SLE disease
activity [45,46,79,80] and anifrolumab, an antibody to the common type I
interferon receptor, has shown ther-apeutic effects [62]. Since the
anifrolumab effect appears to be largely dependent on the presence of the
interferon signature [62], this will likely become a more routine parameter
in the near future. However, using it for regular monitoring would
presumably need a more practical test system.
6.2. IL-6
While clearly pro-inflammatory and increased in active SLE, IL-6 is not
constantly correlated with SLE disease activity [33]. This may in part be
due to a relatively short half-life and a circadian rhythm of IL-6 [81], so that
CRP, which still reflects IL-6, usually is the better and more robust
parameter. In SLE, however, as discussed above, CRP does not function
as an inflammatory marker of the disease. Despite the measurment
issues, IL-6 is elevated not only in sera of patients with active SLE, but
also in cerebrospinal fluid (CSF) of patients with neuropsychiatric
involvement [82,83]. Furthermore, indications of efficacy of both IL-6
receptor blockade with tocilizumab [84] and the Jak inhibitor baricitinib [85],
which among other targets IL-6 receptor signaling, further support its role.
IL-6 was originally found to peak in the very early morning [74], but now
shown to be highest in the later afternoon in a more recent meta-analysis
[75]. Based on its peaking approximately 6 h earlier than CRP, IL-6 is a
parameter used for early infection screening in neonates [86,87], which is
therefore routinely available in many centers. For SLE, however, the
association with (inflammatory) disease activity is not robust enough to
make routine use likely, and issues with the circadian variation would have
to be overcome, which also appears difficult in a routine setting.
6.3. IL-18 and IL-18 binding protein (IL-18BP)
IL-18 is a pro-inflammatory cytokines signaling via NFÿB and MAP
kinases and known to induce IFNÿ production, which is increased in
several autoimmune diseases [88–90]. IL-18 is clearly elevated in active
SLE [67,70,89,91,92] and in patients with lupus nephritis [93–95]. IL-18 is
also among the cytokines that are directly correlated with SLE disease
activity [67,70,91,96] and may therefore be useful as in-inflammatory
markers. Not only the cytokine IL-18 is upregulated in SLE, but so is
IL-18BP [91,92,95], which is again associated with active nephritis [92,95].
Still, not only IL-18BP bound IL-18 is increased, but also free IL-18 [91].
While IL-18BP is relevant in binding the cytokine, IFNÿ, which is typically
downstream of IL-18, leads to IL-18BP tran-scription [97], forming a
negative feedback loop. Both could therefore theoretically work as partly
interdependent markers of inflammatory disease activity. For the time
being, however, this is more of a scientific concept than a parameter likely
to enter clinical routine in the near future.
6.4. TNF and soluble TNF receptor 2 (sTNFR2)
TNF is a strong pro-inflammatory cytokine, which is high in active SLE
and well correlated with disease activity [12,33]. TNF thus probably still
constitutes the best inflammatory marker in this group [19].
TNF is directly induced by immune complexes [9] and has also been
shown highly expressed in SLE inflammatory organ disease, such as in
lupus nephritis. Despite a potential negative immunoregulatory role of the
cytokine [98,99], TNF blockade with both infliximab [100,101] and
etanercept [102] has shown indications of efficacy. While measuring
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Journal of Autoimmunity xxx (xxxx) xxxx
TNF is possible, and can be done with various assays, there is significant
between assay variation, and measurements have not been found reli-
able enough for routine purposes, which may again be partly due to
complex TNF kinetics. Of interest, sTNFR2 levels, which are associated
with both TNF and disease activity [33,103–105], may be more robust and
more feasible parameter. While again not established for routine monitoring,
sTNFR2 measurement would be a good candidate based on scientific data.
6.5. Chemokines
Serum or plasma chemokines, like most of the cytokines, are easily
measured by ELISA technology. While chemokines, usually made in
response to cytokines, are more indirect markers of the inflammatory
process, there are data on the association with disease activity. CCL2/
MCP-1, CXCCL10/IP-10 and CCL19 are known to be interferon-in-ducible
genes, which has led to a composite score estimating interferon activity
associated with SLE disease activity [106,107], similar to the interferon
signature mentioned above . Several other groups have previously found
CCL2 [96,108,109] and CXCL10 [96,110] increased in active SLE. These
chemokines could be one way to depict the interferon in-fluence in SLE.
In addition to these chemokines, at least CCL-11 [109], CXCL13 [111] and
CXCL16 [112] were also associated with disease activity, and serum IL-8
[96], CCL17 [113], CXCL16 [114] and CX3CL1 [109] were associated with
active lupus nephritis.
7. Urinary markers of inflammation
Renal involvement is of particular importance in the monitoring of SLE.
On the one hand, lupus nephritis is the by far most frequent dangerous
organ manifestation of the disease. On the other hand, lupus
glomerulonephritis is largely asymptomatic in many cases, and biopsies
cannot easily be repeated in shorter intervals. Laboratory monitoring
therefore is key, both for detecting new onset renal involvement and for
assessing nephritis activity under therapy.
7.1. Urinary protein and urinary albumin
Given that damage to the glomeruli leads to various degrees of
proteinuria in all sorts of lupus nephritis, which in essence is immune
complex nephritis, proteinuria is the classical marker of SLE kidney
disease. Indeed, the SLE activity scores rely heavily on proteinuria to
estimate nephritis activity (Table 2). Furthermore, reduction of proteinuria
to less than 700–800 g per day is associated with a good renal prognosis
[115]. Quantification of urinary protein thus is essential for following
patients with lupus nephritis [116]. For practicability, spot urine pro-tein/
creatinine ratios have replaced 24 h urine measurements in many situations
[117]. Proteinuria mostly is albuminuria in lupus nephritis, with other
proteins playing a minor role. Indeed, albuminuria is a simple, but useful
marker in detecting lupus nephritis activity [118,119].
Despite its clinical importance, proteinuria and albuminuria have one
critical problem, and that is the inability to reliably distinguish between
ongoing inflammation and damage. Renal damage can also lead to
relevant amounts of urinary protein. On the other hand, residual
inflammatory activity and the amount of treatable proteinuria may be
underestimated [100], and the indirect way of estimating lupus ne-phritis
activity by means of serum supplements and autoantibody levels is of
limited reliability. Therefore, additionally and optimally better urinary
markers are warranted.
7.2. Urinary cytokines and chemokines
The analysis of further urinary proteins, more directly associated with
inflammation, might have value above measuring gross proteinuria or
albuminuria. Candidates mostly are cytokines and chemokines,
Machine Translated by Google
M. Aringer
Table
5 Current and hopeful candidate biomarkers for SLE overall inflammatory
activity and for lupus nephritis. sTNF-R2 soluble tumor necrosis factor receptor-2.
Lupus inflammatory Lupus nephritis activity
activity
Current routine ESR Proteinuria
markers CRP (mostly infection) Albuminuria
Anemia (of chronic Renal histology (large
disease) intervals)
Candidate markers Interferon signature Urinary lymphocytes
sTNF-R2
100A12
which can be easily measured by ELISA. The proinflammatory cytokine
IL-6 was found increased in the urine of patients with active lupus nephritis
[120], as was IL-10 [121], which may play more of an auto-immune than
immunoregulatory role in human SLE. Increased urinary IL-18 levels were
also found in patients with lupus nephritis [92].
However, the urinary cytokine data are only partially convincing, which
may be due to aspect of stability and dilution. Somewhat more likely,
urinary chemokines could play a role. For example, the CC chemokine
ligands CCL2, CCL4, CCL5, CCL8 are increased in the urine of patients
with active as compared to inactive lupus nephritis, as are the CXC
chemokine ligands CXCL9/MIG, CXCL10 and CXCL16 [120,122] .
7.3. Cells in the urine
The analysis of the urinary sediment has for a long time been an
essential aspect in diagnosing lupus nephritis and in roughly estimating
lupus nephritis activity. Indeed, lupus activity scores contain leukocy-turia,
hematuria and cylinders as markers of renal activity (Table 2).
Dysmorphic erythrocytes, damaged by being pressed through the cap-
pillars, and cellular cylinders are specific for active nephritis. How-ever,
proper analysis of the urinary sediment needs significant experience, and
glucocorticoids can rapidly mask abnormalities. On the other hand,
leukocyturia commonly occurs in simple cystitis. Therefore, today there
are tendencies to remove the sediment from definitions of complete renal
remission for scientific studies [123]. This does not preclude using urinary
erythrocytes for the early detection of new onset lupus nephritis, but limits
the use of the urinary sediment for further monitoring under therapy.
More novel approaches take advantage of flow cytometry, which can
be employed for urinary leukocytes as well as for those in peripheral
blood. At least to some degree, urinary leukocytes are reflective of the
leukocyte population within the glomeruli. Urinary T cells, in particular,
have been shown to help in distinguishing active and inactive lupus
nephritis [124–127], and the evaluation of these cells in my view has the
potential for a routine parameter in monitoring lupus nephritis.
These lymphocytes would also be more direct evidence of active ne-
phritis than increased chemokines leading to their influx into the kid-
neys.
8. Conclusions
As in many other respects, SLE remains a highly interesting, complex
disease, also with regard to inflammation and inflammatory markers. The
immune complexes containing nucleic acids on the one hand induce
severe inflammation via conventional pro-inflammatory path-ways,
including cytokines such as TNF and IL-6. On the other hand, the same
immune complexes induce the production of type I interferons and of
various immunoregulatory cytokines. These then modify the immune
response in a relatively characteristic way. The simple con-sequence is a
reduced production of CRP in active SLE, despite in-creased IL-6, which
is visible in concomitant infection. The ESR remains
6
Journal of Autoimmunity xxx (xxxx) xxxx
as a crude parameter, but also includes immunoglobulin, and thus au-
toimmune in addition to inflammatory aspects. Despite many attempts,
and despite many potential markers that are highly increased in active
SLE, a really satisfactory solution has not yet been established, so that
the clinical assessment of inflammation maintains its essential role.
Some of the candidate biomarkers, however, in my view have potential of
entering this field in the near future. Among these are the interferon
signature, the S100 protein A12 and soluble TNF-R2, as well as urinary
lymphocytes for lupus nephritis (Table 5). There is hope that novel markers
will lead to an improved standard of care in the future.
9. Dr. Smolen from my personal view
Dr. Josef Smolen, Joschi, became my boss in 1995, when he was
appointed Professor of Medicine (Rheumatology) and Head of the
Department of Rheumatology at what was then the University of Vienna
and later became the Medical University of Vienna. I still re-member his
early days there, when rather harsh feedback in the weekly Monday
rounds made sure everyone complied with adequate medical
documentation. At the same time, Prof. Smolen had an almost im-mediate,
and very positive impact on abstracts, publications and our overall scientific
output. While I was already working on SLE with Dr.
Winfried Graninger, Prof. Smolen taught us to leave the surface of
phenomenological observation and dig into more mechanistical con-cepts
of cause and effect. He also led us to be more precise in writing, with
manuscripts going countless rounds before deemed worthy of submission.
It was also Dr. Smolen who established my contact with the National
Institute of Arthritis and Musculoskeletal and Skin disease (NIAMS), where
he himself had part of his scientific training. My two plus years there with
Dr. John O'Shea have been essential for my further career. The NIH years
have also been among the best my wife and I have had, and this was in
part due to Dr. Ira Green and his wife Terry, whom Joschi made sure we
met in the very first week there. While I was the first of his team to work
and train at NIAMS, many others have followed in going to the NIH.
Back in Vienna, my scientific focus shifted to cytokines, and I was
entrusted with both increasing medical responsibilities and the conduct of
the first clinical trials of TNF blockade in SLE. When I left Vienna in the
beginning of 2017, following a call to become the professor of Medicine
(Rheumatology) at the TU Dresden, I could still count on him as a mentor.
Joschi also opened doors to the rheumatoid arthritis world, which would
otherwise probably have remained closed to me. It is usually a good sign
for a mentor when both staying at the Department and leaving for better
things are equally attractive, which in Joschi Smolen's case has led his
crew spreading even beyond Austrian borders.
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