Primary anterior cruciate ligament repair-morphological and quantitative assessment by 7-T MRI and clinical outcome after 1.5 years.

OBJECTIVES: The purpose of this study was to assess morphological and quantitative changes of the anterior cruciate ligament (ACL) and cartilage after ACL repair. METHODS: 7T MRI of the knee was acquired in 31 patients 1.5 years after ACL repair and in 13 controls. Proton density-weighted images with fat saturation (PD-fs) were acquired to assess ACL width, signal intensity, elongation, and fraying. T2/T2* mapping was performed for assessment of ACL and cartilage. Segmentation of the ACL, femoral, and tibial cartilage was carried out at 12 ROIs. The outcome evaluation consisted of the Lysholm Knee Score and International Knee Documentation Committee (IKDC) subjective score and clinical examination. RESULTS: ACL showed a normal signal intensity in 96.8% and an increased width in 76.5% after repair. Fraying occurred in 22.6% without having an impact on the clinical outcome (Lysholm score: 90.39 ± 9.75, p = 0.76 compared to controls). T2 analysis of the ACL revealed no difference between patients and controls (p = 0.74). Compared to controls, assessment of the femoral and tibial cartilage showed a significant increase of T2* times in all ROIs, except at the posterolateral femur. Patients presented a good outcome in clinical examination with a Lysholm score of 87.19 ± 14.89 and IKDC of 80.23 ± 16.84. CONCLUSION: T2 mapping results suggest that the tissue composition of the ACL after repair is similar to that of a native ACL after surgery, whereas the ACL exhibits an increased width. Fraying of the ACL can occur without having any impact on functional outcomes. T2* analysis revealed early degradation at the cartilage. CLINICAL RELEVANCE STATEMENT: MRI represents a noninvasive diagnostic tool for the morphological and compositional assessment of the anterior cruciate ligament after repair, whereas knowledge about post-surgical alterations is crucial for adequate imaging interpretation. KEY POINTS: • There has been renewed interest in repairing the anterior cruciate ligament with a proximally torn ligament. • T2 times of the anterior cruciate ligament do not differ between anterior cruciate ligament repair patients and controls. • T2 mapping may serve as a surrogate for the evaluation of the anterior cruciate ligament after repair.

Cinematic rendering in rheumatic diseases-Photorealistic depiction of pathologies improves disease understanding for patients.

Background: Patient education is crucial for successful chronic disease management. Current education material for rheumatic patients however rarely includes images of disease pathologies, limiting patients' disease understanding. Cinematic rendering (CR) is a new tool that allows segmentation of standard medical images (DICOMs) into pictures that illustrate disease pathologies in a photorealistic way. Thus CR has the potential to simplify and improve the explanation of disease pathologies, disease activity and disease consequences and could therefore be a valuable tool to effectively educate and inform patients about their rheumatic and musculoskeletal disease (RMD). Objectives: To examine the feasibility of creating photorealistic images using CR from RMD patients depicting typical rheumatic disease pathologies and, in a second step to investigate the patient-perceived educational potential of these photorealistic images in clinical routine. Methods: We selected conventional, high-resolution (HR) and positron emission tomography (PET) computed tomography (CT) images of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), and giant cell arteritis (GCA) that showed typical respective disease pathologies. These images were segmented using CR technique. In a prospective study, physicians used CR-enhanced and conventional original images to explain the depicted pathognomonic pathologies to patients with the respective rheumatic disease. Patients were then asked to complete a questionnaire evaluating the perceived usefulness of being presented with CR-enhanced images to better understand their underlying disease. Results: CR images were successfully generated from above mentioned CT methods. Pathologies such as bone erosions, bony spurs, bone loss, ankylosis, and PET-based inflammation could be visualized in photorealistic detail. A total of 79 patients (61% females) with rheumatic diseases (RA 29%, PsA 29%, axSpA 24%, GCA 18%) were interviewed and answered the quantitative questionnaire. Mean age was 55.4 ± 12.6 years. Irrespective of disease, all patients agreed or highly agreed that CR-based images help to improve disease understanding, should be shown at disease onset, provide a rationale to regularly take medication and would like to have access to their own CR-enhanced images. Conclusion: Conventional disease images can successfully be turned into photorealistic disease depictions using CR. Patients perceived CR images as a valuable addition to current patient education, enabling personalized disease education and potentially increased medication adherence.

Concise report: a minimal-invasive method to retrieve and identify entheseal tissue from psoriatic arthritis patients.

OBJECTIVES: To establish a minimally invasive biopsy technique for the analysis of entheseal tissue in patients with psoriatic arthritis (PsA). METHODS: Human cadavers were used for establishing the technique to retrieve tissue from the lateral humeral epicondyle enthesis (cadaveric biopsies). After biopsy, the entire enthesis was surgically resected (cadaveric resections). Biopsies and resections were assessed by label-free second harmonic generation (SHG) microscopy. The same technique was then applied in patients with PsA with definition of entheseal tissue by SHG, staining of CD45+immune cells and RNA extraction. RESULTS: Entheseal biopsies from five cadavers allowed the retrieval of entheseal tissue as validated by the analysis of resection material. Microscopy of biopsy and resection sections allowed differentiation of entheseal, tendon and muscle tissue by SHG and definition of specific intensity thresholds for entheseal tissue. In subsequent entheseal biopsies of 10 PsA patients: the fraction of entheseal tissue was high (65%) and comparable to cadaveric biopsies (68%) as assessed by SHG microscopy. Furthermore, PsA biopsies showed immune cell infiltration and sufficient retrieval of RNA for further molecular analysis. CONCLUSION: Entheseal biopsy of the lateral epicondyle is feasible in patients with PsA allowing reliable retrieval of entheseal tissue and its identification by SHG microscopy.

Changes in T2 Relaxation Time Mapping of Intervertebral Discs Adjacent to Vertebrae after Kyphoplasty Correlate with the Physical Clinical Outcome of Patients.

(1) Background: To assess whether clinical outcomes correlate with tissue changes in the intervertebral discs (IVDs) after kyphoplasty as treatment for vertebral fractures, quantitative MRI was applied. (2) Methods: Quantitative T2 mapping acquired in a 3 T MRI scanner of the thoracolumbar spine was performed in 20 patients two years after kyphoplasty. The IVDs adjacent and nonadjacent to the treated vertebrae were divided into six regions of interest (ROI), which were further categorised into inner (ROI 2-5) and outer (ROI 1 and 6) parts of the IVDs, and the T2 values were analysed. T2 values of adjacent discs were correlated with the items of questionnaires evaluating the clinical outcome (i.e., 36-Item Short Form Survey). (3) Results: Lower T2 values in adjacent IVDs correlated with poorer physical outcome two years after kyphoplasty. The inner part of the IVDs adjacent to treated vertebrae showed statistically significant lower T2 values in segments L2/L3 and L3/L4 compared to nonadjacent ones. Patients with lower T2 values showed more pain and physical limitations in everyday life. (4) Conclusions: Quantitative T2 mapping can detect IVD degeneration in patients after kyphoplasty and correlates with the physical outcome. This technique could help to gain better insights into alterations in tissue composition following kyphoplasty and the consequences for the patients' quality of life.

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.

OBJECTIVES: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. RESULTS: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. CONCLUSIONS: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.

Regions at Risk in the Knee Joint of Young Professional Soccer Players: Longitudinal Evaluation of Early Cartilage Degeneration by Quantitative T2 Mapping in 3 T MRI.

PURPOSE: The study aims to detect regions at risk for (pre-)osteoarthritis in the tibiofemoral joint of young professional soccer players by evaluating cartilage composition by T2 mapping in a 3 T magnetic resonance imaging setting. METHODS: In this longitudinal study, 20 professional adolescent soccer players were included. Tibiofemoral cartilage was assessed by quantitative T2 mapping and T2 values were evaluated by regions of interest analysis. Statistical evaluation, using Wilcoxon signed-rank tests, was performed to compare global T2 values and subregional T2 values between a baseline and a follow-up investigation 4.3 years later. Based on the average of playing time (15 years) we divided the cohort in 2 groups and differences were evaluated. RESULTS: When comparing baseline and follow-up, our findings showed statistically significant increases of the global medial tibial and femoral T2 values. The most noticeable results of the subregional T2 analysis were statistically significant increases in the medial posterior zones (deep femoral 36.1 vs. 39.5, P = 0.001; superficial femoral 57.0 vs. 62.4, P = 0.034; deep tibial 28.3 vs. 34.1, P = 0.009; superficial tibial 43.2 vs. 55.3, P = 0.002). CONCLUSION: The elevation of T2 values in the medial, especially medial posterior, compartment of the knee joint indicates that these regions are at risk for early cartilage degeneration already at the time of adolescence. The findings can help individualize and optimize training concepts and to be aware of the chronic stress on these vulnerable areas. Prevention programs should be established in young players to avoid further cartilage damage.

T2 Mapping as a New Method for Quantitative Assessment of Cartilage Damage in Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with damage of the articular cartilage and the periarticular bone. While imaging of bone damage has substantially improved in recent years, direct imaging of the articular cartilage of the hand joints in patients with RA is still challenging. The study used T2 mapping of the finger joints to assess cartilage damage in RA. METHODS: Magnetic resonance imaging (MRI) at 3 Tesla was done in 30 patients with RA, and T2 relaxation times visualizing alteration in the collagen network and hydration of articular cartilage were mapped in 6 cartilage regions of the metacarpophalangeal (MCP) joints 2 and 3. Values were related to autoantibody status [anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF)], disease duration, and disease activity as well as sex and age of the patients. RESULTS: T2 relaxation times could be reliably measured in the 6 regions of the MCP joints. Significantly higher relaxation times indicating more advanced cartilage alterations were observed in the metacarpal heads of ACPA-positive (p = 0.001-0.010) and RF-positive patients (p = 0.013-0.025) as well as those with longer disease duration (> 3 yrs; p = 0.028-0.043). Current disease activity, sex, and age did not influence T2 relaxation times. CONCLUSION: These data show that cartilage damage can be localized and quantified in the hand joints of patients with RA by T2 mapping. Further, ACPA and RF positivity as well as disease duration appear to be the crucial factors influencing cartilage damage.

Quantitative T2 Mapping Shows Increased Degeneration in Adjacent Intervertebral Discs Following Kyphoplasty.

OBJECTIVE: A minimally invasive treatment of osteoporotic and nonosteoporotic thoracic and lumbar spine fractures is cement augmentation (kyphoplasty). Little is known about the impact on adjacent intervertebral discs. A quantitative magnetic resonance imaging (MRI) approach in addition to morphological MRI is desirable to evaluate changes in the intervertebral disc. Our study aims to evaluate the feasibility of T2 mapping for the detection of subtle changes in the intervertebral discs in spines after kyphoplasty. DESIGN: Intervertebral discs were assessed by quantitative MRI (3.0 T) using T2 relaxation time mapping. Region of interest (ROI; 6 per disc) analyses were performed. The ROIs at the anterior and posterior edges were interpreted as annulus fibrosus (AF). The 2 very inner zones were regarded as nucleus pulposus (NP) and the regions in between as intermediate transition zone. We compared T2 relaxation time values of intervertebral discs adjacent to the vertebrae after kyphoplasty with those nonadjacent to vertebrae after kyphoplasty, especially in the NP. RESULTS: The analysis of the ROIs showed that the intervertebral discs of the adjacent vertebral segments are associated with reduced T2 values compared to those that are nonadjacent to the affected vertebrae. CONCLUSION: This study is to our knowledge the first investigation of intervertebral discs after kyphoplasty by quantitative MRI. Quantitative T2 mapping shows increased degeneration in adjacent intervertebral discs following kyphoplasty. Besides its contribution to a broader knowledge of postoperative changes after kyphoplasty, our findings may help to improve differentiation between healthy and degenerated intervertebral discs using these techniques.

Modular Lattice Constructs for Biological Joint Resurfacing.

IMPACT STATEMENT: The repair of large articular cartilage lesions is still a major challenge. In particular, the fixation of the grafts to the subchondral bone plate represents an unresolved problem. In this work, we present a completely novel concept based on a modular lattice, combining building blocks of different ceramic materials, anchoring pins and space for cell-loaded hydrogels or other scaffold materials. This concept targets not only circumscribed cartilage defects but also large osteoarthritic lesions. It spans the bridge between cell therapy and artificial joint arthroplasty, and thus is of significant medical and socioeconomic impact.

Using Cartilage MRI T2-Mapping to Analyze Early Cartilage Degeneration in the Knee Joint of Young Professional Soccer Players.

OBJECTIVE: To evaluate and characterize the appearance of articular cartilage in the tibiofemoral joint of young professional soccer players using T2-relaxation time evaluation on magnetic resonance imaging (MRI). DESIGN: In this study, we included 57 male adolescents from the youth academy of a professional soccer team. The MRI scans were acquired of the knee joint of the supporting leg. An "early unloading" (minute 0) and "late unloading" (minute 28) T2-sequence was included in the set of images. Quantitative T2-analysis was performed in the femorotibial joint cartilage in 4 slices with each 10 regions of interest (ROIs). Statistical evaluation, using Wilcoxon signed-rank tests, was primarily performed to compare the T2 values of the "early unloading" and "late unloading." RESULTS: When comparing "early unloading" with "late unloading," our findings showed a significant increase of T2-relaxation times in the weightbearing femoral cartilage of the medial (P < 0.001) and lateral (P < 0.001) compartment of the knee and in the tibial cartilage of the medial compartment (P < 0.001). CONCLUSION: In this study, alterations of the cartilage were found with a maximum in the medial condyle where the biomechanical load of the knee joint is highest, as well as where most of the chronic cartilage lesions occur. To avoid chronic damage, special focus should be laid on this region.

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFß signalling.

OBJECTIVES: We have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor ß (TGFß) signalling that mediates the antifibrotic effects of the sGC. METHODS: Human fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGFß. sGC knockout fibroblasts were isolated from sGCI(fl/fl) mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-ß1 receptor. RESULTS: sGC stimulation inhibited TGFß-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGFß-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGFß target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGFß-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGFß target gene expression, confirming that non-canonical TGFß pathways mediate the antifibrotic sGC activity. CONCLUSIONS: We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGFß signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.

3D-isotropic high-resolution morphological imaging and quantitative T2 mapping as biomarkers for gender related differences after matrix-associated autologous chondrocyte transplantation (MACT).

The aim of this study was to determine in vivo high-resolution morphological and biochemical gender related differences in cartilage repair tissue (MACT). Forty patients were examined clinically and by MR scans at 3T-MRI (coronal 3D True-FISP sequence for morphologic assessment and multi-echo spin-echo T2-mapping for biochemical assessment of healthy cartilage and MACT cartilage). Mean T2 values in repair tissue in the deep zone showed significantly shorter T2 times in females (p = 0.009, female 43.5 ± 9.8 vs. male 48.2 ± 7.7 ms). The superficial zone showed higher T2 values than the deep zone in both the groups (female 48.5 ± 9.8, males 52.6 ± 11.0 ms) without significant difference between female and male patients. Native control cartilage showed no statistically significant differences for T2 between females and males. The subdivisions "structure of the repair tissue" and "subchondral bone" of the MOCART score showed statistically significant differences between females and males (p = 0.026 and p = 0.007) as well as the Lysholm score (p = 0.03). Our investigations revealed differences between female and male patients after MACT of the knee in clinical outcome and advanced morphological and biochemical MRI. The presented imaging biomarkers can depict subtle changes after cartilage regeneration procedures and might help to understand gender related differences after cartilage repair procedures.

Impact of different coils on biochemical T2 and T2* relaxation time mapping of articular patella cartilage.

OBJECTIVE: The purpose of our study was to assess T2 and T2* relaxation time values of patella cartilage in healthy volunteers using three different coils at 3.0 Tesla MRI and their influence on the quantitative values. METHODS: Fifteen volunteers were examined on the same 3-Tesla MR unit using three different coils: (i) a dedicated eight-channel knee phased-array coil; (ii) an eight-channel multi-purpose coil, and (iii) a one-channel 1H surface coil. T2 and T2* relaxation time measurements were prepared by a multi-echo spinecho respectively a gradient-echo sequence. A semi-automatic region-of-interest analysis was performed for patella cartilage. To allow stratification, a subregional analysis was carried out (deep-superficial cartilage layer). Statistical analysis-of-variance was performed. RESULTS: The mean quantitative T2 values showed statistically significant differences in all comparison combinations. The differences between the mean quantitative T2* values were slightly less pronounced than the T2 evaluation and only the comparison between (i) and (ii) showed a significant difference. The results of T2 and T2* values showed, independent of the used coil, higher values in the superficial zone compared to the deep zone (p < 0.05). Looking at the signal alterations, all coils showed clearly higher values (and thus more signal alterations as a sign of noise) in the deep layer. The validation of the reliability showed a high intra-class correlation coefficient and hence a very high plausibility (ICC was between 0.870 and 0.905 for T2 mapping and between 0.879 and 0.888 for T2* mapping). CONCLUSIONS: The present results demonstrate that biochemical T2 and T2* mapping is significantly dependent on the utilized coil.