Value of MRI - DWI in Assessment of Disease Activity in pulmonary parenchymatous lokalization of Sarcoidosis

Sarcoidosis is an idiopathic, inflammatory disease characterized by the
formation of non-caseous granulomas. In about two-thirds of patients there is a
spontaneous remission of the disease, whereas 10-30% of patients experience a
chronic or progressive course.
In symptomatic patients with a new presentation of sarcoidosis and the presence
of typical intrathoracic abnormalities on imaging and/or biopsy, there is no
doubt regarding the presence of active disease. However, in sarcoidosis
patients with chronic pulmonary consolidations and persisting symptoms, the
assessment of disease activity is more difficult as symptoms of dyspnoea and
fatigue are aspecific and may be caused by old fibrotic changes as well as by
ongoing, active inflammation. A gold standard for identification of active
inflammation is currently lacking. According to the ATS/ERS/WASOG consensus
report 1 active disease is defined as clinical symptoms w/wo active formation
of granulomas w/wo immunological biomarkers w/wo progression to fibrosis and is
thus based on the combination of clinical markers, biochemical markers,
pulmonary function, imaging and/or histopathology.
The presence or absence of active disease has important therapeutic
implications, because active inflammation can be treated with immune
suppressive therapy (prednisone, infliximab) whereas chronic fibrosis is
treated with supportive care. The ability to assess disease activity allows
selective administration of immune suppressive therapy (TNFα inhibitors) and
response monitoring during therapy.

Recent studies show that 18F-FDG PET is able to detect active inflammation
within chronic pulmonary consolidations in patients with sarcoidosis.2,3 In
newly diagnosed patients, Keijsers et al found a sensitivity of 97% of 18F-FDG
PET in identifying sarcoidosis activity. 3 In a systematic review of Treglia
et al regarding the emerging role of 18F-FDG PET as a marker of disease
activity, two important conclusions were: 1) 18F-FDG PET seems to be a very
useful molecular imaging method in assessing disease activity, in staging and
identifying occult sites, and in monitoring treatment response in patients with
sarcoidosis and 2) 18F-FDG PET shows a better diagnostic accuracy compared to
67Ga scintigraphy in patients with sarcoidosis, based on the higher
sensitivity.4 Milman et al. have shown that disease activity, as shown by
18F-FDG PET uptake, decreased during treatment with TNFα inhibition
(adalimumab) compared to pre-treatment FDG uptake.8

An important drawback of 18F-FDG PET is the radiation burden. The effective
dose is estimated to be 4,4 mSv for PET alone, 13,5 mSv for combined PET /
non-diagnostic CT and 14 to 25 mSv for combined FDG PET / diagnostic CT
(depending on scan parameters).9, 10 For a combined FDG PET / diagnostic CT
study, the lifetime attributable risk of cancer incidence was estimated 0.231
to 0.514% for a 20-year old female and 0.163 to 0.323% in a 20-year old male.
Because sarcoidosis patients are usually young or middle aged adults, a
non-radiation emitting study such as MRI would be preferred to assess and
monitor sarcoidosis activity.

Diffusion weighted MR imaging visualizes the movement of water molecules within
biological tissues. The ability of water molecules to diffuse is dependent on
the characteristics of the particular tissue they reside in. The presence of
intracellular organelles, macromolecules, and integrity of cell membranes cause
diffusion of intracellular water molecules to be more restricted than that of
water molecules in the extracellular space. The degree of diffusion restriction
of water molecules is an intrinsic tissue property, and is reflected in the
signal intensity on DWI. Diffusion can be quantified by calculating the
apparent diffusion coefficient (ADC value). DWI has an important, established
role in the detection of acute cerebral ischemia, in abdominal MRI, and in
imaging of pancoast tumours. Its use in thoracic and oncological imaging is
growing. Studies have shown diffusion weighted imaging (DWI) valuable in
differentiating between benign and malignant pulmonary nodules and lymph nodes,
and between lung carcinoma and post obstructive atelectasis 5,11. Furthermore,
(whole-body) MRI with DWI can be used for N- and M-staging in patients with
non-small cell lung cancer, and a number of studies have shown an accuracy
comparable to FDG-PET 6,7. Currently, the value of DWI in sarcoidosis (or any
other interstitial lung disease) has not yet been investigated.

In areas with active inflammation, cellularity is higher than in fibrotic
regions, which means that the ratio between the intra- and extracellular
compartment is larger in inflammation compared to fibrosis. The diffusion of
water molecules will be more restricted in inflamed areas than in fibrosis.

Our hypothesis is that it is feasible to detect active inflammation with DWI in
patients with a new presentation of sarcoidosis and to differentiate active
inflammation from fibrosis in patients with chronic pulmonary infiltrates
(compared to 18F-FDG PET). We also believe it is feasible to detect
intrathoracic lymph node localizations of sarcoidosis.

Most pathologic processes, such as tumor and inflammation, lead to an increase
in T1 and T2 relaxation times. Fibrosis causes shortening of T2. The imaging
sequense STIR TSE (short T1 inversion recovery turbo spin-echo) is very
sensitive to changes in T1 and T2. Recent studies have shown STIR to be more
sensitive than DWI in detecting pulmonary malignancies and in differentiating
different subtypes of adenocarcinoma.12 In a large, prospective cohort, Ohno et
al. found STIR imaging more sensitive and accurate than DWI and integrated
18F-FDG PET-CT in the N-stage assessment of patients with NSCLC.13
In our protocol, we have added a STIR TSE sequence to investigate whether it is
possible to differentiate between inflammation and fibrosis based on
differences in T1 and T2 relaxation times.

Primary Objectives:
1. Is it feasible to visualize active inflammation in patients with pulmonary
sarcoidosis by using Diffusion Weighted Imaging when compared to 18F-FDG PET?

Secondary Objectives:
1. Is it feasible to visualize lymph node localisation of sarcoidosis by using
Diffusion Weighted Imaging when compared to 18F-FDG PET?
2. Is there a relationship between the contrast ratio of parenchymatous
sarcoidosis on STIR and metabolic activity as assessed by 18F-FDG PET?
3. Is there a relationship between enhancement of parenchymatous sarcoidosis on
MRI and metabolic activity as assessed by 18F-FDG PET?

This is an observational (pilot) study in sarcoidosis patients who undergo a
18F-FDG PET scan for detection of active inflammation.
The proportion of active inflammation found with 18F-FDG PET and DWI will form
the basis for a sample size calculation needed for a larger validation study.

Patients with a new presentation of pulmonary localized sarcoidosis are
included (n=10), as well as patients with chronic pulmonary infiltrates
secondary to active inflammation or fibrosis (n=10).
MRI with DWI is added to the regular work-up of these patients, which includes
laboratory investigation, pulmonary function tests, a CT scan of the chest and
a 18F-FDG-PET scan.

Burden: MRI scan of the thorax (duration 45 minutes).

The risk is equal to that of a regular MRI scan with intravenous contrast and
relates to the presence of a strong magnetic field.
Patients will be asked to fill in the regular contra-indication form prior to
the MRI scan. Prior to the MRI scan renal function will be assessed.

There is no direct personal benefit for participants.
If results are favourable, we expect a benefit for sarcoidosis patients as a
group, because then an non-radiation examination would make detection and
monitoring of sarcoidosis activity possible.