PRediction Of Flares In Lupus with autoantibodiEs and chemokines (PROFILE)

Systemic lupus erythematosus (SLE) is a chronic relapsing-remitting autoimmune
disease with a wide range of clinical manifestations affecting several organs.
Although the management of lupus patients has improved in the last years,
accurate models for predicting disease progression are lacking.
In clinical practice, SLE patients can be categorized into three groups:
1. A large group of patients has *quiescent* disease; after diagnosis of SLE
and possibly a short induction treatment with corticosteroids, patients remain
in a state of remission for years with hydroxychloroquine treatment only.
2. A substantial group of patients has relapsing-and-remitting disease, with
mostly cutaneous inflammation but without further organ involvement.
3. A smaller group of patients has severe inflammation with extensive organ
involvement, including lupus nephritis and neuropsychiatric SLE (npSLE) as the
most threatening complications.
This stratification of patients is reflected by the frequency of hospital
visits. Patients with more severe disease activity have a higher frequency of
visits to the outpatient clinic and more frequently receive biologicals.(1) In
the UMC Utrecht, patients in group 1. normally visit the outpatient clinic on a
yearly basis, patients in group 2. visit 2-4 times a year and patients in group
3. are seen more frequently. However, some patients with quiescent disease for
years can still present with an SLE exacerbation, and patients with frequent
bouts of inflammation can eventually reach a remission state.
It would be of great value to be able to distinguish these patient categories
early after diagnosis. This would aid the clinician in identifying those
patients who can safely visit the outpatient clinic only once a year, and
conversely, it would be possible to point out which patients should be
monitored more closely. Ideally, this early distinction would also correspond
with treatment decisions, that is, intensifying treatment when a flare is
suspected, or tapering medication when there is a low risk profile. The
ultimate goal would be to enable clinicians to identify high risk patients and
to treat them with immunomodulating therapy before any inflammatory damage has
occurred, for instance with the combination of rituximab and belimumab as is
being studied right now.(2,3)
The pathogenesis of SLE is highly complex. Genetic predispositions,
proinflammatory and anti-inflammatory cytokines, autoantibodies, lymphocyte
subset abnormalities as well as defects in the complement systems all have
putative roles in the development of SLE. At present, tools that enable early
patient stratification are lacking. Furthermore - except for a possible
association of rise in anti-dsDNA-antibodies and the development of lupus
nephritis - factors that can predict SLE flares have not been identified.
Active disease has a large impact on the life of SLE patients, since it is
known to result in a lower health-related quality of life.(4) Fatigue is an
important factor in patient reported quality of life, but interestingly,
disease activity is not associated with fatigue.(5) This can lead to a
discrepancy, where the clinician assesses the patient*s disease activity to be
under control, where the patient is still experiencing a large burden of
disease. Due to lack of objective parameters correlating with patient reported
outcomes, this discrepancy is difficult to interpret for physicians.
When considering factors that can be relevant for patient risk stratification,
the role of (novel) autoantibodies in the pathogenesis of SLE should not be
overlooked. Several autoantibodies have been shown to be of diagnostic value
for SLE (anti-dsDNA, anti-SmD, anti-Rib-P, anti-PCNA, anti-Chromatin,
anti-complement (C1q)) and changes in the level of autoantibodies can reflect
disease activity.(6) However, dynamics of antibody levels on their own are
insufficient to be used as predictors of lupus activity in individual patients.
Moreover, some types of treatment, such as B-cell targeted therapy, are known
to influence the dynamics of antibody levels, making them harder to interpret.
Some chemokines and matrix metalloproteases (MMPs) and their inhibitors (TIMPs)
have been shown to provide an indication of subclinical injury or inflammation
in other inflammatory diseases and in renal inflammation.(7-9) For example,
urinary CXCL9 levels were found to be associated with risk of acute rejection
of renal transplants and a decline in renal function.(10) In addition, serum
levels of CXCL10 have been shown to correlate with lupus activity in patients
with SLE.(11) Furthermore, urinary levels of CXCL10 have shown very promising
results in the early detection of allograft rejection in kidney transplants.
Currently, an international randomized controlled trial is investigation if
early treatment of rejection, detected by urinary CXCL10, will improve
outcomes. (12) As of yet, these urinary markers have not been studied in the
context of SLE and lupus nephritis. Dynamic levels of these urine markers and
the relation to their corresponding serum levels could serve as early
indicators of nephritis.

The primary objective of this study will be to prospectively evaluate the
predictive value of a combination of chemokines, MMPs/TIMPs, and autoantibody
levels for predicting flares in patients with SLE. This approach allows
identification of the markers with the best predictive value.
As a secondary objective, this study will investigate whether dynamic changes
in autoantibody- and chemokine levels differ between patients treated with or
without anti-B-cell therapy (for instance, with rituximab or belimumab). In
patients treated with anti-B-cell therapy lower autoantibody levels are
observed, which could influence the combination of markers being studied. Until
now, it is unclear whether the degree of lowering autoantibody levels after
treatment is correlated with treatment efficacy and whether changes in
autoantibody levels in SLE patients treated with anti-B-cell therapy can be
indicative of lupus flares. This study will give insight into this
relationship.
We will also assess the relationship of these biomarkers with patient reported
quality of life and fatigue. These markers might provide the physicians extra
tools on how to interpret the discrepancy between objective measurements by the
physician and patient reported outcomes.

This is a prospective, observational single centre cohort study, conducted at
the department of Rheumatology and Clinical Immunology of the UMC Utrecht.
Included patients will be followed for 2 years. First measurements will be
performed at baseline, follow-up measurements will be performed every 3 months.
Data from baseline measurement will be used to investigate a cross-sectional
research question (RQ4). As this is an observational study, treatment decisions
will be left to the discretion of the treating physician.
At the first visit, informed consent will be collected from the patient. At the
first visit, the patients* medical history and medication history will be
collected. If not performed historically in the last 12 months, laboratory
assessments for antinuclear antibodies (ANA) will be performed, as well as
specification of found ANA*s by lineblot assay, as well as screening for
antiphospholipid antibodies (aPL). The acquired damage in patients with SLE is
scored with the SLICC-ACR Damage Index, which will be repeated at the last
visit of the patient.
At each visit, the disease activity of the patient will be assessed by the
study physician, using the SLEDAI-2K, PGA and SLE Flare Index (SFI). Blood and
urine samples will be collected at every visit, to examine for presence of
autoantibodies and chemokines. Patients will be requested to fill out two
questionnaires, the LupusQoL and the Fatigue severity scale. Utilization of
health care services and changes in medication will be evaluated at every
visit. Weight and blood pressure are measured every visit, as well as routine
lab evaluation. Cardiovascular risk screening is performed annually. An
overview of all study procedures is presented in table 1. All collected data
will be used to answer RQ1-RQ3.
The data from the measurements from the D1 visit will be used to answer RQ4.
Patients will be stratified in three risk groups based on a combination of
number of outpatient clinic visits, hospital admittances and intensity of
immunosuppressant therapy (dose of prednisone, use of DMARDs, biologics,
cyclophosphamide) in the year before inclusion. The risk groups are the
low-risk (quiescent) group, the intermediate (relapsing-remitting) risk group,
and the high-risk (severe inflammation) group. Newly diagnosed patients
(diagnosis <1 year), for whom insufficient information is available to
accurately stratify at the beginning of the observational period, will also be
included as a separate fourth group.
This allocation is based on 4 variables: outpatient clinic visits,
hospitalizations, medication use and amount of prednisolone used.
Hydroxychloroquine (HCQ) is the basis of treatment for all patients with SLE.
If treatment with HCQ is not sufficient, (low dose) prednisolone and/or other
immunnosuppressants are used. A small number of patients experience severe
flares despite immunosuppressant therapy and are subsequently treated with
biologicals, such as belimumab or rituximab.
Patients will be stratified in the highest group corresponding to the
allocation criteria. For specific analyses, patients in group 3 will be split
into two subgroups, patients receiving anti-B-cell therapy (3a) and patients
who do not receive anti-B-cell therapy (3b).

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