due to difficulty with participant recruitment and data futility

Background:

Inflammation plays a significant role in various disorders that involve neurodegeneration or autoimmune reaction as one of their mechanisms. PET scans can help detect inflammation. Two new drugs may create better PET images.

Objective:

- To see if the drug [11C]MC1 can help image inflammation.

Eligibility:

• People age 18 and older with rheumatoid arthritis or idiopathic inflammatory myopathy (IIM).
• Healthy volunteers enrolled in protocol 01-M-0254 or 17-M-0181 are also needed.

Design:

• Healthy participants will be screened under protocol 01-M-0254 or 17-M-0181.
• Participants with arthritis or IIM will have a screening visit. This will include:
• Medical history
• Physical exam
• Blood and urine tests
• Possible CT or X-ray: A machine will take pictures of the body.
• Healthy participants will have 1 or 2 visits. They may have urine tests. They may take the drug celecoxib by mouth. They will have a PET scan. A small amount of one or both study drugs will be injected through a catheter: A needle will guide a thin plastic tube into an arm vein. Another catheter will draw blood. They will like on a bed that slides into a machine. Their vital signs and heart activity will be measured.
• Participants with arthritis will have up to 2 visits after screening. They may take celecoxib and have PET scans.
• Participants with IIM will have up to 3 visits after screening. At 1 or 2 visits, they will take celecoxib and have PET scans. They will have 1 visit where they have an MRI: They will lie on a table that slides into a machine. The machine takes pictures of the body.

I. Objective

18-kDa translocator protein (TSPO) and cyclooxygenase-2 (COX-2) are both implicated in the pathophysiology of various inflammatory disorders, suggesting that both may serve as potential biomarkers of inflammation in brain as well as periphery. Our laboratory recently developed two new radioligands: [11C]ER176 to image TSPO and [11C]MC1 to image COX-2. Using wholebody imaging, this study seeks to determine whether PET imaging using these new radioligands can differentiate two inflammatory conditions-rheumatoid arthritis (RA) and idiopathic inflammatory myopathies (IIM)-from healthy conditions. To determine if [11C]MC1 uptake is specific to COX-2, we will also conduct a blocking study with a selective COX-2 inhibitor (celecoxib) in both [11C]MC1 and [11C]ER176 scans; celecoxib is expected to block uptake of [11C]MC1 but not [11C]ER176. Using brain-dedicated imaging, this seeks to determine whether RA patients and healthy volunteers have specific binding in brain - i.e., uptake that can be blocked celecoxib.

II. Study population

Healthy volunteers (n = 17), patients with RA (n = 15), and patients with IIM (n = 15) will undergo whole-body PET/CT scans. Patients with AxSpA (n=15) will undergo two whole-body PET/MRI scans. In addition, healthy volunteers (n = 22) and patients with RA (n = 12) will have brain-dedicated imaging using [11C]MC1 concurrent with arterial blood sampling. Finally, 15 patients with RA will be imaged during a period of moderate to severe symptoms and after clinically indicated treatment for two to four months. Thus, the entire population will be healthy volunteers (n = 39), patients with RA (n = 42), patients with AxSpA (n=15) and patients with

IIM (n = 15).

III. Design

1. Phase 1: We will begin by injecting up to 10 mCi of [11C]MC1 in one healthy male and one healthy female and then conducting a whole body PET scan. Uptake will be measured in the ovaries and testes, and the dose of radioactivity will be calculated. We will proceed only if the dose to these organs with the higher injected activity proposed for Phase 2 will not exceed the limits specified by the Radioactive Drug Research Committee (RDRC).
2. Phase 2: Fifteen RA patients, 15 IIM patients, and 15 age-, sex-, and genotype-matched healthy subjects will undergo two whole-body PET/CT scans using 15 mCi of [11C]ER176 on one day and two whole-body PET/CT scans using 15 mCi of [11C]MC1 on another day. The first scan on each day will serve as the baseline scan for comparison; the second scan on each day will be a blocking study using celecoxib. The [11C]ER176 scans are not mandatory and will be requested at the discretion of the PI.
3. Phase 3: Twelve RA patients and 22 age- and sex-matched healthy subjects will undergo two brain-dedicated PET/CT scans, each using 20 mCi [11C]MC1, and concurrent with arterial blood sampling. The first scan will be a baseline scan, and the second will be after blockade by celecoxib.
4. Phase 4: Fifteen RA patients will be imaged twice with [11C]MC: while having moderate to severe symptoms and after clinically-indicated therapy for about two to four months. Participants will have whole-body scan after injection of 15 mCi of [11C]MC1.

IV. Outcome measures

For whole body imaging, radioligand uptake in a selected region of interest will be quantified as a Standardized Uptake Value (SUV), which normalizes for injected activity and body weight. Possible differences in actual blood radioligand level will be adjusted by venous blood data obtained during the PET scan. Regional uptake after blockade with celecoxib will be expressed as a percentage of the baseline value. The baseline uptake and the percentage blockade by celecoxib of each radioligand will be compared between patients and healthy subjects as well as between inflamed and non-inflamed regions of the body in RA and IIM patients.

For brain-dedicated imaging, the density of COX-2 will be measured with pharmacokinetic modeling and expressed as distribution volume (VT).

• INCLUSION CRITERIA:

Healthy subjects

• Aged 18 years or older.
• Willing and able to complete all study procedures.
• Able to provide informed consent.
• Healthy based on medical history, physical examination, and laboratory testing.
• Enrolled in protocol 01-M-0254 The Evaluation of Participants with Mood and Anxiety Disorders and Healthy Volunteers or 17-M-0181 Recruitment and Characterization of Healthy Research Volunteers for National Institute of Mental Health (NIMH) Intramural Studies.
• Be age and sex-matched with patient groups for the 15 subjects in the Phase 2.

RA patients

• Aged 18 years or older.
• Willing and able to complete all study procedures.
• Able to provide informed consent.
• Have been given a diagnosis of RA based on the published criteria (Aletaha et al., 2010).
• Have moderate to severe symptoms, as defined by a Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) score >3.2, but RA patients may be in remission for the repeat scan in phase 4.

IIM patients

• Aged 18 years or older
• Willing and able to complete all study procedures.
• Able to provide informed consent.
• Meets Bohan and Peter criteria ((Bohan and Peter, 1975a, b) for probable or definite dermatomyositis (DM) or polymyositis (PM), or
• Meets criteria for inclusion body myositis (IBM) as defined by Lloyd et al.: 1) finger flexor or quadriceps weakness, and 2) endomysial inflammation, and 3) either invasion of non-necrotic muscle fibers or rimmed vacuoles.

Axial Spondyloarthritis (AxSpA) patients

• Aged 18 years or older.
• Willing and able to complete all study procedures.
• Able to provide informed consent.
• Have been given a diagnosis of AxSpA based on Assessment of Spondylo-Arthritis International Society (ASAS) criteria AxSpA.

EXCLUSION CRITERIA:

1. Common for all participants

   • Because non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2, subjects should not have taken NSAIDs or willow bark tea for two weeks prior to the PET scan.
   • For Phase 2, 3 and 4 *contraindications to taking COX-2 inhibitors that, in the opinion of the investigators, have the potential to affect the results or the safety of the participant.

   These may include:

   • History of hypersensitivity reaction to COX inhibitors or History of aspirin- or NSAID-induced asthma

   • History of upper or lower gastrointestinal bleeding, gastritis, peptic ulcer disease

   • History of uncontrolled gastroesophageal reflux disease (GERD), but not medically controlled GERD

   • Coagulation disorder

   • Thrombocytopenia

   • Glucose-6-phosphate dehydrogenase (G6PD) deficiency

   • History of gout

   • History of hepatic or renal impairment

   • History of cardiovascular disease or presence of cardiovascular risk factors such as uncontrolled or poorly controlled hypertension

   • Current use of probenecid

   • Patients clinically in remission or who have low disease activity

     • Positive HIV infection

     • Any other history of severe medical illness or injury with the potential to affect study data interpretation or to be any medical contraindication to the procedures performed in the study, including active infection and untreated malignancy.

     • Unable to travel to NIH

     • Recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.

     • Inability to lie flat on camera bed for at least two hours, including claustrophobia and overweight greater than the maximum for the scanner (500 lb.).

     • Pregnancy or breastfeeding.

     • Participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not exclusion criteria, unless that use affects the function of daily life.

     • NIMH employees or an NIH employee who is a subordinate/relative/co-worker of the investigators.

       • These criteria will not be applied to the two healthy volunteers participating in the Phase 1 of this study*.

2. Healthy subjects

   • Clinically significant laboratory abnormalities based on tests performed under screening protocol 01-M-0254 or 17-M-0181.

3. AxSpA and IIM patients

   • Unable to have an MRI scan (e.g., pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or shrapnel fragments, metal fragments in the eye).

This study will also comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule.

18 months after study closure

De-identified data can be accessed through NIH Biomedical Translational Research Information System (BTRIS)