Multiparametric Quantitative MRI for the Detection of IgA Nephropathy Using Tomoelastography, DWI, and BOLD Imaging.

OBJECTIVES: The aim of this study was to noninvasively evaluate changes in renal stiffness, diffusion, and oxygenation in patients with chronic, advanced stage immunoglobulin A nephropathy (IgAN) by multiparametric magnetic resonance imaging using tomoelastography, diffusion-weighted imaging (DWI), and blood oxygen level-dependent (BOLD) imaging. MATERIALS AND METHODS: In this prospective study, 32 subjects (16 patients with biopsy-proven IgAN and 16 age- and sex-matched healthy controls) underwent multifrequency magnetic resonance elastography with tomoelastography postprocessing at 4 frequencies from 40 to 70 Hz to generate shear wave speed (meter per second) maps reflecting tissue stiffness. In addition, DWI and BOLD imaging were performed to determine the apparent diffusion coefficient in square millimeter per second and T2* relaxation time in milliseconds, respectively. Regions including the entire renal parenchyma of both kidneys were analyzed. Areas under the receiver operating characteristic (AUCs) curve were calculated to test diagnostic performance. Clinical parameters such as estimated glomerular filtration rate and protein-to-creatinine ratio were determined and correlated with imaging findings. RESULTS: Success rates of tomoelastography, DWI, and BOLD imaging regarding both kidneys were 100%, 91%, and 87%, respectively. Shear wave speed was decreased in IgAN (-21%, P < 0.0001), accompanied by lower apparent diffusion coefficient values (-12%, P = 0.004). BOLD imaging was not sensitive to IgAN (P = 0.12). Tomoelastography detected IgAN with higher diagnostic accuracy than DWI (area under the curve = 0.9 vs 0.8) and positively correlated with estimated glomerular filtration rate (r = 0.66, P = 0.006). CONCLUSIONS: Chronic, advanced stage IgAN is associated with renal softening and restricted water diffusion. Tomoelastography is superior to DWI and BOLD imaging in detecting IgAN.

US Time-Harmonic Elastography for the Early Detection of Glomerulonephritis.

Background Glomerulonephritis refers to renal diseases characterized by glomerular and tubulointerstitial fibrosis. Multifrequency US time-harmonic elastography enables the noninvasive quantification of tissue elasticity. Purpose To assess the diagnostic performance of US time-harmonic elastography for the early detection of glomerulonephritis. Materials and Methods From August 2016 through May 2017, study participants with biopsy-proven glomerulonephritis were prospectively examined with US time-harmonic elastography. Participants were subdivided according to chronic kidney disease (CKD) stage. All participants underwent elastography of both kidneys to generate full-field-of-view maps of renal shear wave speed (SWS). SWS was determined separately for the whole renal parenchyma, cortex, and medulla and was correlated with quantitative B-mode findings such as renal length and parenchymal thickness. Diagnostic performance of renal elastography was assessed with receiver operating characteristic curve analysis. Results Fifty-three participants with glomerulonephritis (mean age ± standard deviation, 49 years ± 14) and 30 healthy volunteers (mean age, 37 years ± 11) were evaluated. Age-adjusted renal SWS was lower in participants with glomerulonephritis than in healthy volunteers in the parenchyma, cortex, and medulla, with mean values of 1.55 m/sec (95% confidence interval [CI]: 1.51 m/sec, 1.59 m/sec) and 1.69 m/sec (95% CI: 1.64 m/sec, 1.74 m/sec; P < .001), respectively, in parenchyma, 1.80 m/sec (95% CI: 1.75 m/sec, 1.84 m/sec) and 2.08 m/sec (95% CI: 2.02 m/sec, 2.13 m/sec; P < .001) in cortex, and 1.25 m/sec (95% CI: 1.21 m/sec, 1.29 m/sec) and 1.33 (95% CI: 1.27 m/sec, 1.38 m/sec; P = .03) in medulla. Age-adjusted renal cortex SWS was lower in participants with glomerulonephritis and stage 1 CKD (preserved renal function) than in healthy volunteers (mean, 1.88 [95% CI: 1.81, 1.96] vs 2.08 [95% CI: 2.02, 2.13]; P < .001). In participants with CKD, renal cortex SWS values showed a positive association with estimated glomerular filtration rate (n = 39; r = 0.56; P < .001). Exploratory diagnostic performance of US time-harmonic elastography (area under the receiver operating characteristic curve [AUC], 0.89; 95% CI: 0.82, 0.97) outperformed that of B-mode parameters such as parenchymal thickness (AUC, 0.64; 95% CI: 0.51, 0.77; P < .001) and renal length (AUC, 0.55; 95% CI: 0.40, 0.68; P < .001) in identifying glomerulonephritis. Conclusion US time-harmonic elastography depicts abnormal renal stiffness in glomerulonephritis, particularly among patients with early disease and preserved renal function. Advanced chronic kidney disease is associated with further cortical softening. Time-harmonic elastography outperforms B-mode-based size quantification. © RSNA, 2019 Online supplemental material is available for this article.

Tomoelastography Paired With T2* Magnetic Resonance Imaging Detects Lupus Nephritis With Normal Renal Function.

OBJECTIVES: The aim of this study was to test multiparametric magnetic resonance imaging including blood oxygen level-dependent (BOLD) imaging by T2* mapping, magnetic resonance elastography (MRE) by tomoelastography, and diffusion-weighted imaging (DWI) for detecting nephropathy in patients with lupus nephritis (LN). METHODS: Forty-one subjects (25 patients with LN and 16 age- and sex-matched healthy volunteers; LN: mean age, 47.3 ± 14.8 years; 22 female subjects; volunteers: mean age, 43.9 ± 11.6 years; 13 female subjects) were prospectively enrolled. The LN group was further divided into subgroups with normal (LN-nRF, GFR > 90 mL/min per 1.73 m) and compromised renal function (LN-cRF, GFR < 90 mL/min per 1.73 m). All subjects were examined by multifrequency MRE, BOLD imaging, and DWI, yielding shear wave speed (SWS; in meter per second), T2* relaxation times (in millisecond), and apparent diffusion coefficient (ADC; in millimeter square per second), respectively. Renal subregional analysis was performed for the medulla (ME), inner cortex (CoI), and outer cortex (CoO). Imaging markers were correlated to clinical parameters such as GFR and protein-to-urine creatinine ratio. Cutoffs and area under the receiver operating curve (AUROC) were computed to test diagnostic performances. RESULTS: Compared with CoI and CoO, LN-nRF predominantly affects ME tissue (SWS: -7%, P < 0.01; T2*: +9%, P < 0.05; ADC: -5%, P = 0.27). Detection of LN-nRF was better with MRE compared with BOLD imaging and DWI (AUROC = 0.81, 0.76, not significant), whereas pairing MRE with T2* further increased diagnostic power (AUROC = 0.91). Disease progression was associated with reduction of SWS also in CoI (LN-nRF, 3.04 ± 0.38 m/s; LN-cRF, 2.60 ± 0.26 m/s; p = 0.013), allowing distinction of LN-nRF from LN-cRF (AUROC = 0.83). Diffusion-weighted imaging was only sensitive to LN-cRF in ME tissue (ADC, -12%; P < 0.05). CONCLUSIONS: Lupus nephritis with normal renal function first arises in MRE and BOLD images within ME tissue, progressing to CoI tissue once renal function becomes impaired and diffusion of tissue water changes.

Who Wears the Pants: The Implications of Gender and Power for Youth Heterosexual Relationships.

Relationships in which power is equally distributed are consistently associated with greater quality (e.g., deeper intimacy, less turmoil, more pleasure), but it can be difficult to strike such a balance. Furthermore, dominant gender scripts and norms are complexly intertwined with power in heterosexual relationships. We studied the joint implications of power and gender for relationship quality using 114 U.S. emerging adults' quantitative and qualitative assessments of 395 heterosexual relationships. Linear mixed method analyses indicated that participants found relationships in which they shared power or were dominant to be more intimate and stable than those in which they felt subordinate, but we found no link between power and pleasure. Gender acted as a moderator such that women rated relationships in which they felt subordinate as less intimate and more tumultuous than those in which they felt dominant, whereas men's ratings did not vary by whether they felt subordinate or dominant. Qualitative data also showed power imbalances to be more problematic for women: Of the 17 relationships involving an abusive or controlling partner, 15 were reported by women. We conclude that while both young men and young women may feel subordinate in relationships, the consequences thereof are more detrimental for young women.

Monocyte alterations in rheumatoid arthritis are dominated by preterm release from bone marrow and prominent triggering in the joint.

OBJECTIVE: Rheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints. We investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints. METHODS: CD14+ cells from BM and peripheral blood (PB) of patients with RA and osteoarthritis (OA) were profiled with GeneChip microarrays. Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilisation. Cytometric profiling determined monocyte subsets of CD14++CD16-, CD14++CD16+ and CD14+CD16+ cells in BM, PB and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum. RESULTS: Investigation of genes differentially expressed between RA and OA monocytes with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+monocytes in RA-PB. Patterns associated with tumor necrosis factor/lipopolysaccharide (TNF/LPS) stimulation were weak and more pronounced in RA-PB than RA-BM. Cytometric phenotyping of cells in BM, blood and SF disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+monocytes in RA-PB. Monocyte activation in SF was characterised by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P. CONCLUSION: Patterns of less mature and less differentiated RA-BM and RA-PB monocytes suggest increased turnover with accelerated monocytopoiesis, BM egress and migration into inflamed joints. Predominant activation in the joint indicates the action of local and primary stimuli, which may also promote adaptive immune triggering through monocytes, potentially leading to new diagnostic and therapeutic strategies.

Characterisation of hand small joints arthropathy using high-resolution MRI--limited discrimination between osteoarthritis and psoriatic arthritis.

OBJECTIVE: To test the hypothesis that microanatomical differences in joint disease localisation could be exploited using high-resolution MRI to better differentiate among rheumatoid arthritis (RA), spondyloarthritis/psoriatic arthritis (SpA/PsA) and osteoarthritis (OA) in clinical practice. METHODS: Sixty-nine patients with suspected inflammatory joint disease of the hand or feet underwent high-resolution MRI using a small loop coil. Images were scored blinded to the clinical status. Various joint changes like periostitis, osteitis, erosions, enthesitis and synovitis were recorded. The image-based diagnosis was compared with the clinical diagnosis. RESULTS: In 59.4 % of the patients the clinical diagnosis was confirmed on image analysis. This was high for OA (80 %), moderately good for RA (67 %) but only 50 % for SpA/PsA. The major difficulty was to distinguish OA from SpA/PsA where common imaging findings are evident including periostitis (SpA/PsA 45 %, OA 40 % compared with RA 0 %; P = 0.015). Likewise, osteitis was frequently detected in SpA/PsA (79 %) and OA (80 %) and less frequently in RA (42 %) (P = 0.014). CONCLUSION: Characterisation of inflammatory disorders of small joints merely using high-resolution MRI remains challenging especially in the differentiation between OA and PsA. These findings are likely explained by common microanatomical similarities in disease expression rather than limitations of imaging techniques. KEY POINTS: • High-resolution MRI is increasingly used to investigate joint disease. • Osteitis and periostitis occur in psoriatic and osteoarthritis (but not rheumatoid arthritis). • In severely affected patients the amount of synovitis and erosions is similar.

Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab.

UNLABELLED: Introduction Takayasu arteritis (TA) is a large vessel vasculitis involving the aorta and its major branches. T cell-mediated autoimmunity is thought to play a major role in its pathogenesis, while the role of B cells is still unclear. METHODS: B cell subsets in the peripheral blood of 17 patients with TA were analysed and compared with nine patients with active systemic lupus erythematosus (SLE) and nine healthy controls by flow cytometry. Based on these findings, three patients with active refractory TA were treated with B cell depletion therapy (BCDT) using monoclonal anti-CD20 antibodies (rituximab). RESULTS: The absolute number and frequency of peripheral blood CD19(+)/CD20(-)/CD27(high) antibody-secreting cells in patients with active TA was significantly higher than in healthy donors. As in active SLE, the majority of these cells are newly generated plasmablasts which significantly correlated with TA activity. Three patients with active refractory TA and expansion of plasmablasts were successfully treated with BCDT, which resulted in remission. CONCLUSION: Disturbances of B cell homeostasis may be critical in TA. Circulating plasmablasts could be a useful biomarker of disease activity and a tool for selecting appropriate candidates for BCDT. B cells and plasmablasts/plasma cells may therefore represent novel targets for effective therapies for TA.

Anti-dsDNA-NcX ELISA: dsDNA-loaded nucleosomes improve diagnosis and monitoring of disease activity in systemic lupus erythematosus.

INTRODUCTION: The objective of this study was to compare the clinical usefulness of the new anti-double-stranded DNA nucleosome-complexed enzyme-linked immunosorbent assay (Anti-dsDNA-NcX ELISA), which is based on dsDNA-loaded nucleosomes as antigens, with established test systems based on dsDNA or nucleosomes alone for systemic lupus erythematosus (SLE) diagnostics and determination of disease activity. METHODS: Sera from a cohort of 964 individuals comprising 207 SLE patients, 357 disease controls and 400 healthy donors were investigated using the Anti-dsDNA-NcX ELISA, Farr assay, Anti-dsDNA ELISA, Anti-nucleosome ELISA and Crithidia luciliae immunofluorescence (CLIF) assay, all of which are tests available from EUROIMMUN Medizinische Labordiagnostika AG (Lübeck, Germany). Receiver operating characteristic curve analyses were performed to compare the sensitivity and specificity of each assay. The test results yielded by these assays in a group of 165 fully characterized SLE patients were compared with the corresponding medical records. RESULTS: The Anti-dsDNA-NcX ELISA was found to have a sensitivity of 60.9% and a specificity of 98.9% in all 964 individuals at the manufacturer's cutoff of 100 U/ml. At a comparable specificity of 99%, the sensitivity amounted to 59.9% for the Anti-dsDNA-NcX ELISA, 54.1% for the Farr assay, 53.6% for the antinucleosome ELISA and 35.8% for the anti-dsDNA ELISA. The CLIF assay had a sensitivity of 28.0% and a specificity of 98.2%. The Anti-dsDNA-NcX ELISA correlated mostly with global disease activity in a cross-sectional analysis. In a longitudinal analysis of 20 patients with 69 patient visits, changes in Anti-dsDNA-NcX ELISA and antinucleosome ELISA results correlated highly with changes in disease activity over time. CONCLUSIONS: The use of dsDNA-complexed nucleosomes as antigens in ELISA leads to optimized determination of diagnosis and disease activity in SLE patients and is available for clinical practice.

Blood dendritic cells in systemic lupus erythematosus exhibit altered activation state and chemokine receptor function.

BACKGROUND: Dendritic cells (DCs) have a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Reduced numbers of blood DCs and the accumulation of DCs at inflammatory sites have been observed in SLE. One crucial feature of DCs is their ability to migrate. OBJECTIVE: To analyse the maturation/activation state and the migratory capacity of different DC precursor subsets in SLE to further elucidate their role in autoimmunity. METHODS: Plasmacytoid DCs (pDCs), myeloid DCs (mDCs) and monocytes from patients with SLE, healthy volunteers and healthy volunteers immunised with tetanus/diphtheria were examined by flow cytometry for expression of subset-specific antigens (BDCA-2, CD11c, CD14, HLA-DR), activation/maturation markers (CD83, CD86, CD40, BLyS) and chemokine receptors (CCR1, CCR5, CCR7, ChemR23). Additionally, migratory capacity to chemokine receptors was investigated in vitro using the chemokines RANTES, CCL19 and chemerin. RESULTS: SLE monocytes and mDCs had higher CD86 and B-lymphocyte stimulatory factor (BLyS) expression levels. ChemR23 expression was lower in SLE pDCs and mDCs. Basal and CCL19-specific migration levels were higher in SLE pDCs. Altered DC function in SLE had no correlative changes in chemokine receptor expression, whereas immunisation-induced blood DC migration patterns in healthy donors were accompanied by changes in chemokine receptor expression. CONCLUSIONS: The phenotypic and migratory disturbances observed in SLE blood DCs could result in altered distribution of DCs in peripheral tissues, contributing to dysregulated immune responses and autoimmunity.

Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus.

OBJECTIVE: Disease activity in systemic lupus erythematosus (SLE) is usually assessed with complex disease activity scores comprising a variety of different parameters. In order to determine whether SLE disease activity correlates with abnormal B lymphocyte activity, B cell subsets were analyzed, and their relationship to clinical and humoral measures of disease activity was assessed. METHODS: The distribution of B cell subsets was determined by fluorescence-activated cell sorting analysis and assessed in relation to the autoantibody profile, disease activity measured by the SLE Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measure scores, disease duration, and therapy. RESULTS: The number and frequency of CD27(high) plasma cells were significantly correlated with the SLE disease activity indices and with the titer of anti-double-stranded DNA (anti-dsDNA) autoantibodies. Circulating B cell subsets were not influenced by age or sex, but appeared to relate to the duration of disease and the therapeutic regimen, with the number and frequency of CD27(high) plasma cells increasing and those of CD27- naive B cells decreasing over time. Patients were divided into those with a SLEDAI score of 0-8 (low disease activity) and those with SLEDAI score >8 (high disease activity). Patients with high disease activity had an increased frequency of both CD19+ B cells and CD27(high) plasma cells. By using a nonparametric data sieving algorithm, we observed that these B cell abnormalities provided predictive values for nonactive and active disease of 78.0% and 78.9%, respectively. The predictive value of the B cell abnormalities (78.9%) was greater than that of the humoral/clinical data pattern (71.4%), including anti-dsDNA antibody levels, circulating immune complexes, increased erythrocyte sedimentation rate, mucocutaneous involvement, and acute renal involvement. CONCLUSION: Flow cytometric monitoring of B cell subsets in the peripheral blood provides new insights into abnormalities of B cell function in SLE and may also be a diagnostically valuable option for monitoring the activity of this autoimmune disease.

Simultaneous cytometric analysis of (auto)antigen-reactive T and B cell proliferation.

The detection and characterization of (auto)antigen-specific lymphocytes, both B and T cells, is essential to investigate immunopathologic mechanisms. Our aim was to perform a CFSE (Carboxyfluorescein diacetate succinimidyl ester)-based cytometric analysis of peripheral blood mononuclear cells (PBMC) proliferating in response to antigenic provocation. CFSE-labeled PBMC were stimulated with a superantigen (SEB), a recall antigen (tetanus toxoid), an allergen (grass pollen) and an autoantigen (nucleosomes) and stained after cultivation with CD4-, CD8- and CD19-antibodies. Proliferated cells were identified cytometrically by the decrease of the CFSE fluorescence intensity due to cell division. Antigen-reactive, proliferated B cells were further analysed phenotypically, antigen-specific proliferated Th cells were further characterized functionally regarding their cytokine secretion pattern after polyclonal restimulation. Using this technique, antigen-specific proliferated B and Th cells were detected even at low frequencies. Analyzing the cytokine secretion pattern of allergen-reactive proliferated Th cells after polyclonal restimulation we found differences in the expression of IL-13 and IL-4 between an atopic and a healthy donor. After stimulation of PBMC from TT-vaccinated donors TT-specific proliferated B cells were detected in high frequencies and showed a plasmablast-typical CD20(low) CD27(high) phenotype with only low frequencies expressing CD138 (= Syndecan-1). Proliferation of nucleosome-reactive Th cells and B cells was observed in both patients and healthy controls. We have optimized here the cytometric analysis of reactive cell proliferation based on CFSE offering various facilities of application on the further characterization of both antigen-specific B and T cells.