FDG PET and optical probe-based imaging of differential aspects of acute inflammation treatment response in mouse rheumatoid arthritis models

Objectives Imaging biomarkers provide an opportunity to assess different mechanistic aspects of acute inflammation non-invasively and may aid decisions in drug discovery. The aim was to validate FDG PET (metabolism) and optical imaging biomarkers (cathepsin and MMP activity) for acute inflammation in mouse models of rheumatoid arthritis (RA).

Methods CAIA RA was induced by IV inj. of a monoclonal antibody cocktail, followed by LPS inj. 6 days later. CIA RA was induced by SC inj. of bovine type II collagen in CFA at the tail base, with a booster 21d later. PET scans of hind paws were acquired 1.5h after IV FDG inj. on the day of control peak disease and recovery. Cathepsin (ProSense;PS) and MMP (MMPSense;MS) (PerkinElmer,MA) activatable fluorescent probes were injected IV 24 hours prior to fluorescence molecular tomography.

Results Dexamethasone (DEX;3mpk;PO;QD) produced near-full disease inhibition in both the CIA and CAIA models, compared to controls (VEH). Methotrexate (MTX;3mpk;PO;QD) produced significant disease inhibition in the CAIA model. Hindpaw activation of MS and PS, and FDG SUV (see Fig) showed increase vs naïve paws and MTX and DEX treated paws. However, celecoxib (CXB;30mg/kg;PO;BID) produced no significant paw swelling and clinical score inhibition and no inhibition of FDG uptake, but moderate inhibition of MS/PS activity.

Conclusions FDG SUV, and MS/PS activation provided reliable biomarkers of acute inflammation and treatment-inhibition, in the CAIA and CIA models. The MS and PS based signals, showed a slight uncoupling for CXB. FDG SUV however, showed no difference between CXB and VEH and a strong correlation with paw selling and clinical score based measurements for all groups. FDG SUV may therefore provide a differential biomarker in RA, compared with MMP and cathepsin based biomarkers. Correlation with histopath is intended, to further advance the validation of these biomarkers for use in pharmaceutical testing