Imaging monitoring

Question 1

What is PET used for (broadly)?

Answer 1

Molecular imaging by Positron Emission Tomography (PET) allows for in vivo visualisation of immune targets at picomolar level. By synthesis of a PET tracer that binds to the target of interest, the target can be visualised in vivo: in animal models and in patients.

Question 2

What does a PET tracer consist of?

Answer 2

A PET tracer consists of a compound of choice (e.g. protein, lipid) that is labeled with a positron emitting radionuclide (e.g. F-18, C-11, Zr-89 or Ga-68). The radiolabel makes the localization of the binding of the compound visible in vivo. The imaging technique allows for in vivo studies of immune targets in the whole body and can guide selected tissue biopsies.

Question 3

What is the principle of PET?

Answer 3

1. I.V. injection of PET tracer that will disseminate through the whole body.
2. Patient is placed on the scanning bed
3. PET scan is made

Question 4

What is the principle of PET at tissue level?

Answer 4

PET tracer is injected in blood vessel. The permeability of the blood vessel at the site of inflammation is larger than normal, so the PET tracer can get into the inflamed tissue where it can bind its receptors on the immune target of interest. Since the tracer is combined with a radionucleotide, it will be visible for the PET camera.

Question 5

What are developments in applications of immune target imaging by PET in rheumatology?

Answer 5

Developments in applications of immune target imaging by PET in rheumatology:
• Early diagnostics of rheumatic diseases (before clinician can determine the disease to allow early (preventive) treatment)
• Early therapy monitoring to predict outcome of treatment
• Development of personalized treatment by in vivo identification of dominant immune profile in the individual patient
• Pathogenetic studies: in vivo investigation of target expression and imaging guided tissue analyses
• Support of development of new therapeutic drugs by radiolabeling of the drug pharmacokinetic and dynamic studies

Question 6

Why are macrophages important in rheumatoid arthritis?

Answer 6

Macrophage infiltration in inflamed joints in RA is important:
•They are present from early development of RA onwards
•They relate to therapy efficacy
•They are systemically involved in inflammation

Macrophages are biomarkers for:
•Disease activity: can be used for early diagnosis
•Response to treatment: can be used for monitoring

Question 7

What are examples of PET tracers investigated for macrophage imaging?

Answer 7

FDG-18F, (R)-PK11195-11C and PEG-folate-18F

Question 8

What is the role of B-cells in rheumatoid arthritis?

Answer 8

They involve plasma cells that synthesize auto-Abs that play a major pathogenetic role like IgM-RF and anti-CCP.
B-cells also secrete cytokines that activate macrophages, fibroblasts and (directly or indirectly) the osteoclasts that damage the bone

Question 9

What is an important target on B-cell and what can be done with it?

Answer 9

Important target on B-cells: CD20
o Can be stained or imaged
o Can be taken up in follecular areas of inflammation
o Anti-CD20 Ab Rituximab is used in clinic to treat RA: Use can be imaged using radio-labelled Rituximab. Clear uptake was seen and it was predictive for clinical outcome

Question 10

Why is fibronectin expression in the rheumatoid arthritis synovium a target for therapy?

Answer 10

•Fibronectin expression is associated with fibroblast activity and with angiogenesis in RA synovium. Both present since early disease.
o Imaging of targeted delivery of IL-10 is possible by binding it to fibronectin in RA
o F8IL10 is a fusion of anti-inflammatory cytokine IL-10 to the antibody fragment. F8 binds to ED-A of fibronectin to allow targeted delivery to RA joints. By labeling F8IL10, in vivo biodistribution of the therapeutic agent can be imaged –>It targeted the inflamed joints (yay!), but also had high uptake in the spleen and liver (??)–> why
o Fibronectin ED-A stainings of spleen and liver in arthritic rats showed a significantly higher uptake of fibronectin in spleen and liver in RA rats compared to healthy rats. Most likely effect of the systemic inflammation.

Question 11

What is spondyloarthritis?

Answer 11

A group of rheumatic diseases with inflammation in the spine and sacro-iliac joints (pelvis)

Question 12

What are the symptoms of spondyloarthritis?

Answer 12

Pain and/or stiffness of the back and neck

Question 13

When does spondyloarthritis start?

Answer 13

Mostly before the age of 45 years

Question 14

Are there good diagnostic tests available for early assessment of spondyloarthritis?

Answer 14

No

Question 15

What is a hallmark of spondyloarthritis?

Answer 15

Bone formation: spine starts looking like bamboo and ankylosis of sacro-iliac joints

Question 16

What is a tool for diagnostics and monitoring spondyloarthritis?

Answer 16

•Imaging of new bone formation is a tool for diagnostics and monitoring of spondyloarthritis
o F-18-fluoride is a PET tracer that has affinity to deposit at areas where the bone is newly mineralising. It is an imaging marker for new bone formation and indirectly for osteoblast activity
o PET-guided biopsies in sponyloarthritis to better understand the histology of the lesions better for development of new therapeutic drugs
Clear difference between histology of PET+ lesion and PET- lesion.
•PET+ lesions had more inflammation, bones connected to each other and new bone formation than in PET- lesions
o Therapy monitoring of spondyloarthritis with F-18-fluoride: useful! Also sensitive to look at changes in bone formation during treatment

Question 17

What are the properties of FDG-18F?

Answer 17

FDG-18F, 110 min half-life. Binds glucose transporter and is used for investigation of glucose metabolism. Accumulates at any site that is metabolically active (mainly macrophages). Highly sensitive, but less specific.

Question 18

What are the properties of (R)-PK11195-11C?

Answer 18

(R)-PK11195-11C, 20 min half-life. Binds to translocater protein (TSPO) formal peripheral benzodiazapin receptor and is used for neuro-inflammation/RA (because it might also be activated on macrophages there)
o PET positivity correlated with synovial macrophage infiltration
o Useful for early diagnostics of RA before clinical arthritis is present. –> improvement possible: scanning whole body and lower noise/signal ratio
o Therapy monitoring: also useful. Can it also predict long-term clinical outcome? Still investigating

Question 19

What are the properties of PEG-folate-18F?

Answer 19

PEG-folate-18F, 110 min half-life. Binds to Folate receptor beta (highly expressed on activated macrophages in RA) and is used for RA and atherosclerosis.
o Detection of arthritis using folate imaging previously shown in ovarium cancer patients
o Anti-folate methotrexate is an anchor drug for treatment of RA
o Significantly higher expression of Folate receptor beta in RA patients both in synovial fluid and tissues
o Binding still very good after radiolabeling
o In rat: also signalling confirmed with histology
o Clear uptake in arthritic joints of the hands of RA patients