Bispecific T cell engager therapy for refractory rheumatoid arthritis.

Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function. Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells. Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.

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.

Semi-quantitative magnetic resonance imaging scoring of the knee detects previous injuries in professional soccer players.

PURPOSE: The medical examination ("medical") is an important procedure in professional soccer since it has high economic relevance. In addition to clinical tests, magnetic resonance imaging (MRI) is used to assess joint health. In the present study, the reliability of semiquantitative knee MRI during the "medical" in professional soccer was tested, and its relationship with clinical data and days missed due to knee injury was observed. METHODS: In this cross-sectional study, between 2012 and 2019, 69 newly assigned players (age 18-35 years) from a professional soccer club underwent MRI (3.0 T) of both knee joints during their "medical". Reported knee injuries and previously missed days due to injury were obtained from player anamnesis and the "transfermarkt.com" database. Based on the established "Whole-Organ Magnetic Resonance Imaging Score" (WORMS), two independent radiologists graded the MRI results. Further evaluation was based on the mean score of both knees. RESULTS: The mean WORMS for all subjects was 13.9 (median 10.5, range 0-61). Players with previous injuries had significantly higher scores than players without reported injuries (22.1 ± 17.7 vs. 8.9 ± 4.4, p < 0.002). Three outliers (previously undetected injuries) in the group of players without reported injuries were observed (6.7%). The WORMS was significantly correlated with a prior knee injury (r: 0.424, p < 0.0001) and days missed due to injury (r: 0.489, p < 0.001). Age was correlated with the WORMS (r: 0.386, p < 0.001). In a linear regression model, prior injury was the only significant predictor of a high WORMS (p = 0.001). The WORMS was a significant predictor of days missed due to injury (p < 0.0002) and prior injury (sensitivity: 78%, specificity: 91%, p = 0.006). The intraclass correlation coefficient was excellent (0.89). CONCLUSION: Semiquantitative knee MRI for WORMS determination during the soccer "medical" is a robust and reliable method. Prior injury, even in players without documented trauma, was detected by the WORMS, and previously missed days due to injury were correlated with the semiquantitative MR knee score. LEVEL OF EVIDENCE: Level III.

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.

Locally renewing resident synovial macrophages provide a protective barrier for the joint.

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1- mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.

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.

Acoustic radiation force impulse tissue characterization of the anterior talofibular ligament: a promising noninvasive approach in ankle imaging.

OBJECTIVES: The anterior talofibular ligament (ATFL) is the most frequently injured ligament during inversion strains of the ankle. The purpose of this study was to evaluate the feasibility of acoustic radiation force impulse (ARFI) elastography and to determine the in vivo mechanical properties of the ATFL in healthy athletes. METHODS: Sixty healthy athletes (32 female, 28 male; 28.9 ± 2.1 years) were recruited from the medical and sports faculty. ARFI values, represented as shear wave velocities (SWVs) as well as conventional ultrasound were obtained for the ATFL in neutral ankle position. A clinical assessment was performed in which the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Score and the functional ankle ability measure (FAAM) were collected. Interobserver and intraobserver reliability (repeated sessions and repeated days) were assessed using an intra class correlation coefficient (ICC) and typical error (TE) calculation in absolute (TE) and relative units as coefficient of the variation (CV). RESULTS: SWV values of the ATFL had an average velocity of 1.79 ± 0.20 m/s for all participants, with an average of 1.72 ± 0.36 m/s for females and 1.85 ± 0.31 m/s for males. The interobserver and intraobserver reliability revealed an ICC of 0.902 and 0.933 (TE of 0.67 (CV: 5.2%) and 0.52 (CV: 3.84%)), respectively. FAAM and AOFAS revealed the best possible scores. CONCLUSION: ARFI seems to be a valuable diagnostic modality and represents a promising imaging marker for the assessment and monitoring of ankle ligaments in the context of acute and chronic ankle instabilities; ARFI could also be used to investigate loading or sport dependent adaptions.

Reduced invasive and muscle-sparing operative approaches to the posterolateral chest wall provide an excellent accessibility for the operative stabilization! : Minimized approaches to the posterolateral chest wall.

PURPOSE: Stabilizing techniques for flail chest injuries are described through wide surgical approaches to the chest wall, especially in the most affected posterior and lateral regions. Severe morbidity due to these invasive approaches needs to be considered due to dissection of the scapular guiding muscles and the risk of injuries to neurovascular bundles. This study discusses possibilities for minimized approaches to the posterior and lateral regions. METHOD: Ten fresh-frozen cadavers in lateral decubitus position were observed on both sides. Each surgical arm was kept mobile during the procedure. Approaches were performed following a standard protocol with muscle-sparing incisions starting with 5 cm in length and extending to 10 and 15 cm. The accessible surface comparing the extensions was measured. Visible ribs were counted. In a next step, MatrixRib® Plates were fixed to those ribs to prove the feasibility of rib stabilization through limited approaches. RESULTS: Combinations of the posterior and lateral minimized approaches allow surgical fixation of 6-9 and 7-11 ribs through 5 and 10 cm incisions, respectively. In the case of an extreme expansion of a rib fracture series, an access extension can be made to 15 cm to be able to adequately supply the entire hemithorax using two approaches. CONCLUSION: Extensive invasive surgical approaches to the thoracic wall can be replaced by reduced invasive and muscle-sparing access combinations. A free-moving positioning of the arm and an accurate preoperative plan for minimizing approaches are essential. Minimally invasive plate techniques are very helpful adjuncts.

Transplantation of Chemically Processed Decellularized Meniscal Allografts.

Objective The aim of this study was to evaluate the chondroprotective effect of chemically decellularized meniscal allografts transplanted into the knee joints of adult merino sheep. Methods Lateral sheep meniscal allografts were chemically processed by a multistep method to yield acellular, sterile grafts. The grafts were transplanted into the knee joints of sheep that were treated by lateral meniscectomy. Joints treated by meniscectomy only and untreated joints served as controls. The joints were analyzed morphologically 6 and 26 weeks after surgery by the macroscopical and histological OARSI (Osteoarthritis Research Society International) score. Additionally, the meniscal grafts were biomechanically tested by cyclic indentation. Results Lateral meniscectomy was associated with significant degenerative changes of the articular cartilage of the lateral joint compartment. Transplanted lateral meniscal allografts retained their integrity during the observation period without inducing significant synovitis or foreign body reactions. Cellular repopulation of the grafts was only present on the surface and the periphery of the lateral meniscus, but was still completely lacking in the center of the grafts at week 26. Transplantation of processed meniscal allografts could not prevent degenerative changes of the articular cartilage in the lateral joint compartment. Compared with healthy menisci, the processed grafts were characterized by a significantly reduced dynamic modulus, which did not improve during the observation period of 26 weeks in vivo. Conclusion Chemically decellularized meniscal allografts proved their biocompatibility and durability without inducing immunogenic reactions. However, insufficient recellularization and inferior stiffness of the grafts hampered chondroprotective effects on the articular cartilage.

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.

Limited integrative repair capacity of native cartilage autografts within cartilage defects in a sheep model.

The purpose of this study was to investigate integration and cellular outgrowth of native cartilage autografts transplanted into articular cartilage defects. Native cartilage autografts were applied into chondral defects in the femoral condyle of adult sheep. Within the defects, the calcified cartilage layer was either left intact or perforated to induce bone marrow stimulation. Empty defects served as controls. The joints were analyzed after 6 and 26 weeks by macroscopic and histological analysis using the ICRS II Score and Modified O'Driscoll Scores. Non-treated defects did not show any endogenous regenerative response and bone marrow stimulation induced fibrous repair tissue. Transplanted native cartilage grafts only insufficiently integrated with the defect borders. Cell death and loss of proteoglycans were present at the margins of the grafts at 6 weeks, which was only partially restored at 26 weeks. Significant cellular outgrowth from the grafts or defect borders could not be observed. Bonding of the grafts could be improved by additional bone marrow stimulation providing ingrowing cells that formed a fibrous interface predominantly composed of type I collagen. Transplanted native cartilage grafts remain as inert structures within cartilage defects and fail to induce integrative cartilage repair which rather demands additional cells provided by additional bone marrow stimulation.

Negative pressure wound therapy to prevent seromas and treat surgical incisions after total hip arthroplasty.

PURPOSE: The purpose of this study was to evaluate the use of negative pressure wound therapy (NPWT) to improve wound healing after total hip arthroplasty (THA) and its influence on the development of postoperative seromas in the wound area. MATERIALS: The study is a prospective randomised evaluation of NPWT in patients with large surgical wounds after THA, randomising patients to either a standard dressing (group A) or a NPWT (group B) over the wound area. The wound area was examined with ultrasound to measure the postoperative seromas in both groups on the fifth and tenth postoperative days. RESULTS: There were 19 patients randomised in this study. Ten days after surgery, group A (ten patients, 70.5 ± 11.01 years of age) developed seromas with an average size of 5.08 ml and group B (nine patients, 66.22 ± 17.83 years of age) 1.97 ml. The difference was significant (p = 0.021). CONCLUSION: NPWT has been used on many different types of traumatic and non traumatic wounds. This prospective, randomised study has demonstrated decreased development of postoperative seromas in the wound and improved wound healing.