The SMART study (Salt-MRI in Arthritis)
A study investigating sodium accumulation in patients with autoimmune arthritis using 7 Tesla MRI

Rheumatoid arthritis (RA), psoriatic arthritis (PsA), peripheral and axial
spondyloarthritis (SpA) and juvenile idiopathic arthritis (JIA) are autoimmune
diseases characterized by joint inflammation that can lead to disability. In
these diseases, the joint tissue (synovium) is infiltrated by immune cells such
as T cells, B cells, and macrophages which produce a variety of
tissue-destructing cytokines. The origin of the autoimmune response in these
disorders has proven difficult to unravel, although epidemiological research
has succeeded in identifying both genetic and environmental factors
contributing to the risk of disease. The best-known predisposing environmental
factor for RA for example, is smoking. Other factors, including diet, have also
been investigated, but their reported effects were generally inconsistent.
Salt may be a potent new factor affecting inflammatory diseases. Recent studies
in animal models and in humans, both in vitro and in vivo, have revealed that
salt, and more specifically sodium, plays an important role in boosting
inflammatory responses. In a seminal study using 23Na magnetic resonance
imaging (MRI) of humans, bacterial skin infection was shown to result in a
remarkable sodium accumulation in the skin (1). This hypertonic
microenvironment led to increased macrophage activation, which is also one of
the hallmarks of synovial inflammation in rheumatic joint diseases.
Furthermore, sodium can lead to the differentiation of T helper 17 (Th17)
cells, which may also play a role in autoimmune diseases in general and
arthritis in particular (2). Intriguingly, patients with chronic hypernatremia
due to central diabetes insipidus have been reported to have more autoimmune
diseases (3). Together, these findings have raised interest into sodium as a
possible risk factor for autoimmune diseases. Two preliminary studies have
shown that high sodium intake was indeed associated with a higher risk of RA,
particularly among smokers (4, 5).
This has led to our hypothesis that salt (sodium) is intimately involved in
driving inflammation in chronic autoimmune inflammatory conditions in humans.
The higher concentration of sodium of could be driven by glycosaminoglycans
(GAGs): GAGs are anions that attract cations such as sodium and in the skin
sodium is stored due to binding to glycosaminoglycans (GAGs) (6), in rheumatoid
arthritis and other forms of arthritis higher concentrations of GAGs are found
as compared to healthy controls (7, 8).
In this project, we therefore aim to elucidate the role of sodium on certain
specific aspects of autoimmune joint disease and non-autoimmune inflammatory
joint disease, hoping to answer several key questions. Does sodium accumulate
locally in inflamed synovium? Do non-inflamed tissues of patients with
autoimmune joint diseases contain higher sodium concentrations compared to
those of healthy controls suggesting that this may have skewed the immune
system of these patients towards an inflammatory state? Is a correlation
present between glycosaminoglycans (GAGs) concentration and sodium
concentration in synovial fluid? And is the sodium concentration in the
inflamed joint correlated with local and systemic inflammatory response?
Clarifying the role of sodium in these disorders holds the promise of
identifying more general immunomodulatory effects of sodium which could play a
role in several other autoimmune diseases. Moreover, the fact that sodium
intake is modifiable via dietary interventions and could thus be used for
future therapeutic applications, adds to the relevance of this project.

To investigate whether patients with autoimmune joint diseases have higher
sodium concentrations in their inflamed joints and in tissues know to act as
sodium storage locations: skin and muscle, as compared to healthy controls.

Secondary Objective:
1. To investigate if sodium concentration in the inflamed joint is correlated
with local and systemic inflammatory response.
2. To investigate if the concentration of GAGs in synovial fluid is correlated
with sodium concentration.

This is an observational case-control study, investigating if patients with
autoimmune arthritis (RA, PsA, SpA or JIA) and patients with gout or pseudogout
presenting with knee arthritis have higher sodium concentrations in their
inflamed joints, skin and muscle, as compared to age- and gender-matched
controls. To measure sodium concentration, 7 Tesla magnetic resonance (MR)
imaging will be performed in patients and controls of the knee. In patients
blood samples and synovial fluid (if an intra-articular injection with
corticosteroids is indicated) will be obtained to investigate if sodium
concentration in the inflamed joint is correlated with local and systemic
inflammatory response, and the concentration of GAGs in the synovial fluid.

Patient with knee arthritis and autoimmune arthritis (RA, PsA, SpA or JIA) or
gout and pseudogout will be included from the outpatient rheumatology clinic of
the LUMC. The comparator group will consist of 50 age-, and sex-matched healthy
controls who are part of the 7 Tesla MRI control cohort (METC protocol number:
P07.096). The study will be performed in the LUMC.

The decision to include patients with different autoimmune joints diseases (RA,
PsA, SpA and JIA) in one study was based on the following considerations:
1) it appears plausible that salt/sodium may have an inflammation-enhancing
effect that is similar among these diseases. It therefore makes sense to
investigate whether increased sodium concentrations exist in inflamed joints
and sodium-storage tissues in all four diseases at once.
2) the aim is to perform this study in a time-efficient manner. Allowing the
inclusion of patients with these different diseases increases the chance of
recruiting a sufficient number of patients in a relatively limited amount of
time.

Next to patients with autoimmune joint disease, patients with non-autoimmune
inflammatory joint disease (gout and pseudogout) will be included in the study
to investigate if sodium influx is similarly present in other types of
inflammatory arthritis.

7 Tesla magnetic resonance sodium imaging is a unique imaging technique
available in the LUMC allowing the visualisation of sodium gradients in vivo.
This project will be performed in collaboration with professor Andrew Webb from
the Gorter facility for 7 Tesla MRI. In a previous project focused on knee
osteoarthritis, the required methodology for imaging sodium in knee joints has
already been established in this facility (9).
Although inflammation of the small joints in the hands and feet can be
considered as more frequent, and more typical for some of these diseases (e.g.
for RA) than inflammation of the knees, we decided to focus on the knee joints
in this project for two reasons:
1) the spatial resolution of MRI will not be sufficient to adequately
distinguish between synovium, cartilage and bone in the small joints of hands
and feet. Since synovial inflammation is the hallmark of these diseases, it is
essential for this project that definitive conclusions can be drawn concerning
the sodium concentration in synovium. This therefore requires imaging of a
large joint such as the knee with a sufficient synovial surface and thickness.
2) the required methodology for imaging sodium in knee joints has already been
established in the LUMC 7 Tesla Gorter facility precluding any uncertainties
about the detection method.

One of the standard treatments for patients presenting with autoimmune knee
arthritis is an intra-articular injection with corticosteroids. However, since
it is unknown whether this might affect the results of the sodium MRI imaging,
it is desirable to postpone injections until after the MRI has been performed.
To avoid a long treatment delay (due to the postponement of intra-articular
injection) in patients participating in this study, the MR imaging will be
performed as soon as possible after inclusion: maximally 5 working days later.

We expect to be able to include the desired 50 patients within a maximum of 3.5
years from the starting date.

7 Tesla MR imaging and venepuncture will be performed, these investigational
procedures are not associated with major additional health risks. Synovial
fluid aspiration will be performed if an intra-articular corticosteroid
injection is clinically indicated. Since an intra-articular injection always
requires a puncture, the synovial fluid aspiration will not lead to an
increased health risk. Therefore a DSMB is not necessary and will not be
established.