First-in-Humans Study of 68Ga-DOTA-Siglec-9, a PET Ligand Targeting Vascular Adhesion Protein 1.

Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A 68Ga-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to γ-counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM software, version 2.2. In addition, a patient with early rheumatoid arthritis was studied with both 68Ga-DOTA-Siglec-9 and 18F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Results:68Ga-DOTA-Siglec-9 was well tolerated by all subjects. 68Ga-DOTA-Siglec-9 was rapidly cleared from the blood circulation, and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range, 0.020-0.024 mSv/MBq). Most importantly, however, 68Ga-DOTA-Siglec-9 was comparable to 18F-FDG in detecting arthritis. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses of other 68Ga-labeled tracers. Injection of 150 MBq of 68Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of 68Ga-DOTA-Siglec-9, such as in trials to elucidate the treatment efficacy of novel drug candidates.

Evaluation of a New Skeletal Troponin I Assay in Patients with Idiopathic Inflammatory Myopathies.

BACKGROUND: The current biomarkers for diagnosis and monitoring of injured and diseased skeletal muscles, such as creatine kinase (CK), have limited tissue specificity and incapability to differentiate between pathological and physiological changes. Thus, new biomarkers with improved diagnostic accuracy are needed. Our aim was to develop and validate a novel assay for skeletal troponin I (skTnI), and to assess its clinical performance in patients with idiopathic inflammatory myopathies (IIM). METHODS: A two-step fluoroimmunoassay was used to analyze samples from healthy reference individuals (n = 140), patients with trauma (n = 151), and patients with IIM (n = 61). RESULTS: The limit of detection was 1.2 ng/mL, and the upper reference limit (90th percentile) was 5.2 ng/mL. The median skTnI concentrations were

The Clinical Impact of Using 18F-FDG-PET/CT in the Diagnosis of Suspected Vasculitis: The Effect of Dose and Timing of Glucocorticoid Treatment.

18F-Fluorodeoxyglucose positron-emission tomography (18F-FDG-PET) with computed tomography (CT) is effective for diagnosing large vessel vasculitis, but its usefulness in accurately diagnosing suspected, unselected vasculitis remains unknown. We evaluated the feasibility of 18F-FDG-PET/CT in real-life cohort of patients with suspicion of vasculitis. The effect of the dose and the timing of glucocorticoid (GC) medication on imaging findings were in special interest. 82 patients with suspected vasculitis were evaluated by whole-body 18F-FDG-PET/CT. GC treatment as prednisolone equivalent doses at the scanning moment and before imaging was evaluated. 38/82 patients were diagnosed with vasculitis. Twenty-one out of 38 patients had increased 18F-FDG accumulation in blood vessel walls indicating vasculitis in various sized vessels. Vasculitis patients with a positive vasculitis finding in 18F-FDG-PET/CT had a significantly shorter duration of GC use (median = 4.0 vs 7.0 days, P=0.034), and they used lower GC dose during the PET scan (median dose = 15.0 mg/day vs 40.0 mg/day, p=0.004) compared to 18F-FDG-PET/CT-negative patients. Vasculitis patients with a positive 18F-FDG-PET/CT result had significantly higher C-reactive protein (CRP) than patients with a negative 18F-FDG-PET/CT finding (mean value = 154.5 vs 90.4 mg/L, p=0.018). We found that 18F-FDG-PET/CT positivity was significantly associated with a lower dose and shorter duration of GC medication and higher CRP level in vasculitis patients. 18F-FDG-PET/CT revealed clinically significant information in over half of the patients and was effective in confirming the final diagnosis.

Joint inflammation related citrullination of functional arginines in extracellular proteins.

We report the extent, specific sites and structural requirements of joint inflammation related citrullination in extracellular proteins. A total of 40 synovial fluid samples derived from chronically inflamed human joints were analysed by heparin-agarose fractionation and LC-MS/MS. Citrullination of 55 arginines in extracellular proteins was detected. Importantly, 20% of the sites have a characterized function related to the hallmarks of destructive joint inflammation. E.g. four arginine residues, shown here to be citrullinated, are also affected by mutations in inherited diseases causing haemolysis or blood clotting dysfunction. Citrullination of integrin ligands was selected for further studies since fibronectin R234 in isoDGR was among the most frequently citrullinated arginines in synovial fluid. Assays with synovial fibroblasts and integrin αVß3 indicated decreased affinity to the enzymatically citrullinated integrin binding sites. To conclude, our data indicate that in inflamed joints extensive citrullination affects the functional arginine residues in extracellular proteins.

Outcomes of switching anti-TNF drugs in rheumatoid arthritis--a study based on observational data from the Finnish Register of Biological Treatment (ROB-FIN).

The aim of this study was to assess, based on observational data from the Finnish Register of Biological Treatment, the outcomes of switching an initial tumor necrosis factor (TNF) blocker to another in the treatment of rheumatoid arthritis (RA). RA patients, who started biological therapy with a TNF blocker between May 1999 and April 2009 and who switched to another TNF blocker, were studied (n=479). The outcomes were assessed according to the reason for and type of the switch. Outcome assessments included American College of Rheumatology 50 responder index (ACR50) response at 3 months after the switch, treatment duration of the second TNF blocker, and swollen joint counts, CRP and DAS28 score at the 3 months, best and last observations of the first and second TNF blocker, respectively. In those who switched due to lack of effectiveness (LOE), the disease activity parameters fell significantly from baseline upon use of infliximab or adalimumab, but had increased prior to the switch. Switching to another TNF blocker (etanercept or adalimumab) restored the response initially achieved with the first TNF blocker. The disease activity parameters fell significantly from baseline upon use of etanercept, and were maintained but not further improved after switching to adalimumab. TNF blocker switching seemed to be most beneficial in secondary LOE (defined as loss of ACR50 response). In those who switched due to adverse events (AE) or other reasons, a similar degree of response as had been achieved with the first agent was also achieved and maintained with the second agent. The results suggest that a second TNF blocker can restore the response in cases of secondary LOE and maintain it after switching due to an AE.