PET-CT of biodistribution of rituximab in relation to therapeutic outcome and histological response of lymphoid tissue in rheumatoid arthritis patients

There is cumulative evidence that B-cells play an important role in the
pathophysiological process of rheumatoid arthritis (RA). Targeted depletion of
B cells with a monoclonal antibody such as rituximab appears to be highly
effective in RA patients (1), also in RA patients refractory to disease
modifying anti-rheumatic drugs (DMARDS) and anti-tumor necrosis factor *alpha
therapy (2). Nevertheless, 30-50% of RA patients does not respond to rituximab
treatment. Treatment could be more effective if potential responders to anti-B
cell therapy could be selected before treatment. Knowledge about tissue
biodistribution in responders / non-responders may help to develop predictive
markers for therapeutic response.
Positron emission tomography (PET) imaging may provide such information.
Information about effects of anti-B cell treatment on lymphoid tissue in RA is
lacking. Therefore, in the current study immunohistochemical staining of
aspirated lymphoid tissue will be performed similar to our previous studies on
synovial tissue (9,10). Histological data will be compared to imaging.

1. To image tissue biodistribution (joints, lymph nodes and internal organs) of
rituximab in RA patients by [89Zr]rituximab PET-CT in RA patients with
clinically active disease that will start rituximab treatment.
2. To investigate whether therapeutic outcome of rituximab treatment is related
to a difference in tissue biodistribution at initiation of treatment by
[89Zr]rituximab and PET-CT.
3. To investigate the relationship between histological response of lymphoid
tissue to rituximab treatment and clinical response as well as PET imaging
results.

Twenty anti-B cell therapy naive RA patients who have a clinical indication for
initiation of anti-B cell treatment will be included. Patients will be treated
with rituximab by the standard clinical infusion schedule (at inclusion (t=0)
and at day 14), followed by infusion of [89Zr]Rituximab at initiation of the
treatment (t=0). PET-CT images will be performed at day 3. In addition, before
rituximab treatment and 4 weeks later, lymphoid tissue will be obtained by
ultrasound-guided inguinal lymph node histological biopsy for
immunohistochemical analysis. Clinical follow-up will be performed up to 24
weeks. PET-CT data will be compared to clinical response and
immunohistochemical data.
Inclusion of patients, infusion of (radiolabeled) rituximab and PET-CT imaging
procedure (including withdrawal of blood samples) as well as clinical follow-up
will be performed at the VU Medical Center (VUMC). The lymph node biopsy and
immunohistochemical investigation of lymphoid tissue will be performed at the
Academic Medical Center (AMC).

1. Radiation exposure
Based on preliminary data of [89Zr]rituximab and other labelled Mabs such as
[89Zr]U36 cMab (effective dose = 0.53 ± 0.03 mSv/MBq (8)), an effective dose of
10 mSv is expected. CT scans used for attenuation correction will give an
additional dose of 2 mSv per patient. The total effective dose is expected to
be around 12 mSv per patient, or about 6 times the yearly natural background
radiation dose in the Netherlands. According to the ICRP-62 model, the risk
level corresponds to *moderate*, while the social benefit is regarded as
*substantial*.

2. Idiosyncratic reaction to the tracer
A low dose of [89Zr]rituximab will be administered. [89Zr]rituximab has been
safely administered to oncology patients. In general, 89Zr-labeled antibodies
have been administered to >100 patients without adverse side-effects.

3. Vena puncture and withdrawal of blood samples
[89Zr]rituximab will be administered intravenously. The necessary vena puncture
is similar to that applied for blood withdrawal in clinical practise. An venous
infusion needle will be placed for withdrawal of blood samples at various time
points, which prevents repeated puncturing of the veins.

4. Discomfort during scanning
It may be uncomfortable to lie motionless on the scanning bed of the PET-CT.
For some patients, the scanning may be anxious. To reduce anxiety and
discomfort as much as possible, patients will be made acquainted with the
surroundings beforehand. In addition, the staff will be present during scanning
and can remove the patient from the scanner if requested.

5. Discomfort during biopsy of lymphoid tissue
After local anesthesia, a small incision will be made in the left or right
inguinal region to perform the biopsy. This leaves a scar of approximately 0.5
cm. There is a small risk of development of a local haematoma, which heals
spontaneously. The whole procedure will take not more than 45 minutes. Prof.
Tak*s group has extensive experience with this approach, which is well
tolerated by the patients and which has been previously approved by AMC*s IRB.