Altered splenic [89Zr]Zr-rituximab uptake in patients with interstitial lung disease not responding to rituximab: could this indicate a splenic immune-mediated mechanism?

Rituximab (RTX) for immune-mediated inflammatory disease (IMID) with interstitial pneumonitis (IP) results in non-response in about a third of patients for reasons not well understood. Complete peripheral B-cell depletion in IMID-IP does not seem to correlate with successful treatment outcome. A hypothesis is that splenic B cells might play a role in B-cell recovery and attraction of naïve B cells in non-responsive patients. The aim of this post hoc analysis of clinical trial data is to search for indicators in [89Zr]Zr-rituximab PET/CT data from the spleen that might explain non-responsiveness. PET/CT data of 20 patients with IMID-IP, who were enrolled in a phase II trial and treated with RTX were analyzed. Clinical outcome was categorized into responders (RSP) and non-responders (NR) after 6 months of initial RTX by two independent pulmonologists. Patients were examined separately to search for associations between clinical outcome, splenic activity on PET/CT, lymphocyte counts and other biomarkers. Treatment failure was found in 6/20 patients (30%) while all patients exhibited B-cell depletion from the circulation. NR patients demonstrated significantly higher splenic activity than RSP patients (non-preload protocol: SUV 4.9±1.96 and SUV 2.3±1.08 respectively, P=0.025). No correlations between treatment outcome and serum lymphocyte subsets were found. Our findings suggest a potential splenic mechanism in IMID-IP patients non-responding to RTX and warrant further consideration and investigation.

[89Zr]Zr-rituximab PET/CT activity in patients with therapy refractory interstitial pneumonitis: a feasibility study.

Recent studies on immune-mediated inflammatory lung diseases show encouraging treatment results with rituximab, a monoclonal antibody (mAb) against CD20-expressing B lymphocytes. The present pilot study aimed to explore the possibility to image CD20-expression in the lungs as future early predictor of treatment response. We describe a series of 10 patients with therapy refractory interstitial pneumonitis who were treated with rituximab (1000 mg at day 0 and day 14) and underwent PET/CT after the administration of [89Zr]Zr-N-suc-DFO-rituximab abbreviated as [89Zr]Zr-rituximab. [89Zr]-rituximab PET/CT of the chest was performed on day 3 and 6. [89Zr]Zr-rituximab PET/CT showed visual and quantifiable increased pulmonary activity in four patients. Other patients demonstrated no increased activity in the lungs. One patient developed a severe allergic reaction during infusion of the first 10% unlabeled rituximab after which rituximab infusion was ceased. Subsequent administration of [89Zr]Zr-rituximab, however, did not result in any adverse reaction. This patient demonstrated the highest uptake of [89Zr]Zr-rituximab in mediastinal lymph nodes and lung parenchyma compared to the other 9 patients who did receive the full dose rituximab before [89Zr]Zr-rituximab. This pilot study demonstrates that [89Zr]Zr-rituximab PET/CT imaging in patients with therapy refractory interstitial pneumonitis is feasible and shows lung-specific uptake in some patients. Further research with larger sample size should establish if the [89Zr]Zr-rituximab uptake correlates with treatment response to rituximab. The higher uptake in the absence of a full 1000 mg rituximab preload may suggest that future studies should consider [89Zr]Zr-rituximab imaging at low mAb dose before treatment with rituximab.

Volumetric FDG PET analysis of global lung inflammation: new tool for precision medicine in pulmonary sarcoidosis?

Currently FDG PET/CT is used as a tool for detection of active sites of sarcoidosis. Routine clinical practice relies on qualitative assessment with visual interpretation. When semi quantitatively expressed, e.g. for scientific purposes, this often leads to dichotomous "positive" or "negative" results. Metabolic activity in the lungs or mediastinum can also be expressed by SUVmax, but this measure is based only on the intensity of a single voxel. Likely for this reason these parameters show poor correlation with variables such as serum biomarkers and suboptimally predict clinical response to treatment. The current study focusses on new volumetric quantification methods for FDG PET/CT. Specifically the percentage of lung volume with increased metabolic activity, "%SUV-high", and the average metabolic activity in the lung "SUVmean", shows significantly better correlation with conventional biomarkers for disease activity than PET dichotomous and SUVmax. Our proposed quantification method needs subsequent and larger studies, however it may open new possibilities for future quantitative research in lung inflammation, and improve precision medicine in sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 44-54).

FDG PET for gauging of sarcoid disease activity.

Fluorodeoxyglucose (FDG), labeled with a positron emitting fluorine-18 ((18)F), is a synthesized glucose analogue and is well known for its application in a wide variety of clinical conditions such as cancer. Visualizing metabolic activity of inflammation is another application of FDG in positron emission tomography (PET). Here, active granulomas appear to have a high affinity for FDG, which is reflected in a high sensitivity of FDG PET imaging. This has led to novel applications of FDG PET in sarcoidosis diagnosis and management. Although chest radiography and high-resolution computed tomography are still the cornerstones of diagnosing pulmonary involvement, FDG PET appears to be superior to both techniques in imaging active sites of disease. FDG PET also correlates well with serum biomarkers such as soluble interleukin-2 receptor in symptomatic patients, and even visualizes active lesions in the context of normal serum biomarkers. Moreover, FDG PET activity in lung parenchyma correlates with decrease of lung function values over time. Also in cardiac involvement in sarcoidosis, FDG PET is a promising technique complementary to magnetic resonance imaging, especially in guiding treatment. New developments, such as applications for quantitative organ-specific measurement, are proceeding and will probably enhance the clinical implementation of FDG PET in sarcoidosis.

Comparison of simplified parametric methods for visual interpretation of 11C-Pittsburgh compound-B PET images.

UNLABELLED: This study compared several parametric imaging methods to determine the optimal approach for visual assessment of parametric Pittsburgh compound-B ((11)C-PIB) PET images to detect cortical amyloid deposition in different memory clinic patient groups. METHODS: Dynamic (11)C-PIB scanning of 120 memory clinic patients was performed. Parametric nondisplaceable binding potential (BPND) images were compared with standardized uptake value (SUV) and SUV ratio images. Images were visually assessed by 3 independent readers, and both interreader and intermethod agreement was determined. RESULTS: Both 90-min (Fleiss κ = 0.88) and 60-min (Fleiss κ = 0.89) BPND images showed excellent interreader agreement, whereas agreement was good to moderate for SUV ratio images (Fleiss κ = 0.68) and SUV images (Fleiss κ = 0.59). Intermethod agreement varied substantially between readers, although BPND images consistently showed the best performance. CONCLUSION: The use of BPND images provided the highest interreader and intermethod agreement and is therefore the method of choice for optimal visual interpretation of (11)C-PIB PET scans.

Polymyalgia rheumatica and interspinous FDG uptake on PET/CT.

Polymyalgia rheumatica (PMR) is an inflammatory disease with macrophage infiltration and CD4+ T-lymphocytes-related mild synovitis commonly causing neck, shoulder, and hip stiffness in patients older than 50 years. Closely related to giant cell arthritis (GCA), PMR symptoms can be similar to rheumatoid arthritis. Erythrocyte sedimentation rate and C-reactive protein levels are elevated in >90% of cases. In 4 patients with PMR, (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) demonstrates uptake in the shoulder and hip joints and also interspinous and supraspinous focal and diffuse uptake. We propose diffuse uptake may reflect ligament inflammation with focal uptake in adjacent interspinous bursitis.