RESUMO
OBJECTIVES: The exact underlying mechanism of rituximab treatment in patients with RA is poorly defined and knowledge about the effect of B cell depletion on immune cells in secondary lymphoid organs is lacking. We analysed lymphoid tissue responses to rituximab in RA patients. METHODS: Fourteen RA patients received 2 × 1000 mg rituximab intravenously, and lymph node (LN) biopsies were obtained before and 4 weeks after the first infusion. Tissues were examined by flow cytometry, immunohistochemistry and quantitative PCR. LN biopsies from five healthy individuals (HC) served as controls. RESULTS: LN biopsies of RA patients showed increased frequencies of CD21+CD23+IgDhighIgMvariable follicular B cells and CD3+CD25+CD69+ early activated, tissue resident T cells when compared with HCs. After treatment, there was incomplete depletion of LN B cells. There was a significant decrease in CD27-IgD+ naïve B cells, and CD27+IgD+ unswitched memory B cells including the CD27+IgD+IgM+ subset and follicular B cells. Strikingly, CD27+IgD- switched memory B cells persisted in LN biopsies after rituximab treatment. In the T cell compartment, a significant decrease was observed in the frequency of early activated, tissue resident T cells after rituximab treatment, but late activated T cells persisted. B cell proliferation inducing cytokine IL-21 was higher expressed in LN biopsies of RA patients compared with HC and expression was not affected by rituximab treatment. CONCLUSION: Rituximab does not cure RA, possibly due to persistence of switched memory B cells in lymphoid tissues suggesting that factors promoting B cell survival and differentiation need to be additionally targeted.
Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Subpopulações de Linfócitos B/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Rituximab/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Biópsia , Feminino , Humanos , Linfonodos/imunologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologiaRESUMO
Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [124I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [124I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [124I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, â¼14-fold higher than that of the control antibody [124I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (â¼7×) fibronectin ED-A expression in these tissues. In conclusion, [124I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [124I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Interleucina-10/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Humanizados , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Humanos , Interleucina-10/genética , Fígado/metabolismo , Masculino , Camundongos , Ratos , Baço/metabolismoRESUMO
Objectives: Excessive bone formation is an important hallmark of AS. Recently it has been demonstrated that axial bony lesions in AS patients can be visualized using 18F-fluoride PET-CT. The aim of this study was to assess whether 18F-fluoride uptake in clinically active AS patients is related to focal bone formation in spine biopsies and is sensitive to change during anti-TNF treatment. Methods: Twelve anti-TNF-naïve AS patients [female 7/12; age 39 years (SD 11); BASDAI 5.5 ± 1.1] were included. 18 F-fluoride PET-CT scans were performed at baseline and in two patients, biopsies were obtained from PET-positive and PET-negative spine lesions. The remaining 10 patients underwent a second 18F-fluoride PET-CT scan after 12 weeks of anti-TNF treatment. PET scans were scored visually by two blinded expert readers. In addition, 18F-fluoride uptake was quantified using the standardized uptake value corrected for individual integrated whole blood activity concentration (SUVAUC). Clinical response to anti-TNF was defined according to a ⩾ 20% improvement in Assessment of SpondyloArthritis international Society criteria at 24 weeks. Results: At baseline, all patients showed at least one axial PET-positive lesion. Histological analysis of PET-positive lesions in the spine confirmed local osteoid formation. PET-positive lesions were found in the costovertebral joints (43%), facet joints (23%), bridging syndesmophytes (20%) and non-bridging vertebral lesions (14%) and in SI joints (75%). After 12 weeks of anti-TNF treatment, 18F-fluoride uptake in clinical responders decreased significantly in the costovertebral (mean SUVAUC -1.0; P < 0.001) and SI joints (mean SUVAUC -1.2; P = 0.03) in contrast to non-responders. Conclusions: 18F-fluoride PET-CT identified bone formation, confirmed by histology, in the spine and SI joints of AS patients and demonstrated alterations in bone formation during anti-TNF treatment.
Assuntos
Antirreumáticos/uso terapêutico , Fluordesoxiglucose F18/farmacologia , Osteogênese/fisiologia , Coluna Vertebral/diagnóstico por imagem , Espondilite Anquilosante/diagnóstico por imagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Biópsia , Feminino , Seguimentos , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/farmacologia , Espondilite Anquilosante/tratamento farmacológico , Adulto JovemRESUMO
PURPOSE: To compare the performance of a convolutional neural network (CNN) to that of 11 radiologists in detecting scaphoid bone fractures on conventional radiographs of the hand, wrist, and scaphoid. MATERIALS AND METHODS: At two hospitals (hospitals A and B), three datasets consisting of conventional hand, wrist, and scaphoid radiographs were retrospectively retrieved: a dataset of 1039 radiographs (775 patients [mean age, 48 years ± 23 {standard deviation}; 505 female patients], period: 2017-2019, hospitals A and B) for developing a scaphoid segmentation CNN, a dataset of 3000 radiographs (1846 patients [mean age, 42 years ± 22; 937 female patients], period: 2003-2019, hospital B) for developing a scaphoid fracture detection CNN, and a dataset of 190 radiographs (190 patients [mean age, 43 years ± 20; 77 female patients], period: 2011-2020, hospital A) for testing the complete fracture detection system. Both CNNs were applied consecutively: The segmentation CNN localized the scaphoid and then passed the relevant region to the detection CNN for fracture detection. In an observer study, the performance of the system was compared with that of 11 radiologists. Evaluation metrics included the Dice similarity coefficient (DSC), Hausdorff distance (HD), sensitivity, specificity, positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC). RESULTS: The segmentation CNN achieved a DSC of 97.4% ± 1.4 with an HD of 1.31 mm ± 1.03. The detection CNN had sensitivity of 78% (95% CI: 70, 86), specificity of 84% (95% CI: 77, 92), PPV of 83% (95% CI: 77, 90), and AUC of 0.87 (95% CI: 0.81, 0.91). There was no difference between the AUC of the CNN and that of the radiologists (0.87 [95% CI: 0.81, 0.91] vs 0.83 [radiologist range: 0.79-0.85]; P = .09). CONCLUSION: The developed CNN achieved radiologist-level performance in detecting scaphoid bone fractures on conventional radiographs of the hand, wrist, and scaphoid.Keywords: Convolutional Neural Network (CNN), Deep Learning Algorithms, Machine Learning Algorithms, Feature Detection-Vision-Application Domain, Computer-Aided DiagnosisSee also the commentary by Li and Torriani in this issue.Supplemental material is available for this article.©RSNA, 2021.
RESUMO
OBJECTIVES: The primary aim is to evaluate signs of inflammation on MRI of sacroiliac joints (SIJ)/spine in inflammatory back pain (IBP) patients suspected of nr-axSpA with high disease activity. Secondary aims are to describe the onset of new inflammatory lesions at MRI after 6 months and to evaluate gender differences in the presence of inflammation. METHOD: Consecutively, patients with IBP with at least two spondyloarthritis features, high disease activity (BASDAI ≥ 4), and who were TNFi naïve, had a MRI of SIJ and spine. In the absence of active lesions, MRI was repeated after 6 months. MRI images were scored according to the Spondyloarthritis Research Consortium of Canada method. RESULTS: Sixty-nine patients were included (53% female), of whom 39% showed signs of inflammation at the first MRI: 30.9% of the SIJ, 19.1% of the spine and 2.4% at both sites, irrespective of the CRP levels. Males more often showed inflammatory signs at the MRI of the SIJ and spine compared with females (45.5% vs. 33.3%). Consistently, the median SPARCC score was higher in males: for SIJ 14.0 (IQR 2.3-25.0) and for spine 11.5 (IQR 8.5-25.6). Only one patient (4.7%) without baseline inflammatory signs showed active lesions of SIJ after 6 months. CONCLUSIONS: Almost 40% of the IBP patients suspected of nr-axSpA, with high disease activity, showed inflammatory lesions on MRI of SIJ and/or spine, which occurred more often in males compared with females. In the majority (95.3%), an MRI without inflammatory lesions remained negative after 6 months despite high disease activity.Key Points⢠Forty percent of inflammatory back pain patients with high disease activity showed inflammatory signs on MRI of the SIJ and/or spine.⢠Only 4% of baseline MRIs without inflammatory signs at baseline conversed to an MRI with inflammatory signs after 6 months.⢠Male inflammatory back pain patients with high disease activity showed more often inflammatory signs on MRI compared with females.
Assuntos
Imageamento por Ressonância Magnética/métodos , Articulação Sacroilíaca/patologia , Coluna Vertebral/patologia , Espondilartrite/diagnóstico , Espondilartrite/patologia , Adulto , Dor nas Costas/etiologia , Feminino , Seguimentos , Humanos , Inflamação/patologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Países Baixos , Índice de Gravidade de DoençaRESUMO
Non-invasive imaging of arthritis activity in rheumatoid arthritis (RA) patients using macrophage PET holds promise for early diagnosis and therapeutic response monitoring. Previously obtained results with macrophage tracer (R)-[11C]PK11195 were encouraging, but the imaging signal could be further improved by reduction of background uptake. Recently, the novel macrophage tracer [18F]fluoro-PEG-folate was developed. This tracer showed excellent targeting of the folate receptor ß on activated macrophages in synovial tissue in a preclinical arthritic rat model. We performed three substudies to investigate the biodistribution, potential for imaging arthritis and kinetic properties of [18F]fluoro-PEG-folate in RA patients. Firstly, biodistribution demonstrated fast clearance of [18F]fluoro-PEG-folate from heart and blood vessels and no dose limiting uptake in organs. Secondly, [18F]fluoro-PEG-folate showed uptake in arthritic joints with significantly lower background and hence significantly higher target-to-background ratios as compared to reference macrophage tracer (R)-[11C]PK11195. Lastly, dynamic scanning demonstrated fast tracer uptake in affected joints, reaching a plateau after 1 minute, co-existing with a rapid blood clearance. In conclusion, this first in man study demonstrates the potential of [18F]fluoro-PEG-folate to image arthritis activity in RA with favourable imaging characteristics of rapid clearance and low background uptake, that allow for detection of inflammatory activity in the whole body.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Receptor 2 de Folato/metabolismo , Ácido Fólico/análogos & derivados , Macrófagos/fisiologia , Polietilenoglicóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Diagnóstico Precoce , Feminino , Radioisótopos de Flúor/farmacocinética , Ácido Fólico/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/metabolismoRESUMO
BACKGROUND: B cells are key players in the pathogenesis of rheumatoid arthritis (RA). Although successful in 50-60% of patients with RA, anti-B-cell therapy given as rituximab could be more efficient by identifying potential responders prior to treatment. Positron emission tomography (PET) using radiolabeled rituximab for B-cell imaging might provide the means to fulfil this unmet clinical need. The objective of this study was to investigate the association between biodistribution of zirconium-89 (89Zr)-rituximab on PET-computed tomography (CT) and clinical response in patients with RA. METHODS: We included 20 patients with RA who were starting rituximab treatment. At the first intravenous (i.v.) therapeutic dose, patients were also injected with 89Zr-rituximab, followed by PET-CT. European League Against Rheumatism (EULAR) response criteria were applied to determine response at week 24. PET-CT was analyzed visually and quantitatively. Lymph node (LN) biopsies were performed at 0 and 4 weeks to correlate B-cell counts with imaging data. RESULTS: PET-positive hand joints (range 1-20) were observed in 18/20 patients. Responders had significantly higher 89Zr-rituximab uptake in PET-positive hand joints than non-responders (median target-to-background (T/B)) ratios (IQR) were 6.2 (4.0-8.8) vs. 3.1 (2.2-3.9), p = 0.02). At T/B ≥4.0, positive and negative predictive values for clinical response were respectively 90% and 75%. Quantitative 89Zr-rituximab hand joint uptake on PET correlated inversely with CD22+ B-cell count in LN tissue at 4 weeks of treatment (r = 0.6, p = 0.05). In addition, the CD22+ B-cell count in LN correlated positively with quantitative LN PET data at baseline, supporting the specificity of B-cell imaging on PET. CONCLUSIONS: Non-invasive B-cell imaging by 89Zr-rituximab PET-CT has promising clinical value to select RA responders to rituximab at baseline. 89Zr-rituximab PET-CT may also hold promise for monitoring anti-B-cell therapies in other B-cell driven autoimmune diseases, such as systemic lupus erythematosus and Sjögren's disease.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Rituximab/uso terapêutico , Adulto , Idoso , Antirreumáticos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioisótopos/farmacocinética , Rituximab/farmacocinética , Distribuição Tecidual , Zircônio/farmacocinéticaRESUMO
INTRODUCTION: Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [18F]FDG and [11C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [18F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference. METHODS: In a stepwise approach different PET tracers were investigated. First, whole body [18F]FDG and [11C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [18F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data. RESULTS: No increased [18F]FDG and [11C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [18F]Fluoride PET-CT, [18F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [18F]FDG depicted only three lesions, with an uptake of five times lower compared to [18F]Fluoride, and again no [11C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [18F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [18F]Fluoride PET positive lesions. CONCLUSIONS: Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [18F]Fluoride. In contrast to active RA, inflammation tracers [18F]FDG and [11C](R)PK11195 appeared to be less useful for AS imaging.