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.

Osteitis and synovitis, but not bone erosion, is associated with proteoglycan loss and microstructure damage in the cartilage of patients with rheumatoid arthritis.

OBJECTIVES: To investigate the relation between anatomic changes of the synovium, the bone, the bone marrow and the cartilage to biochemical properties of the cartilage in patients with rheumatoid arthritis (RA). METHODS: 33 patients with RA received 3-T MRI scans of the metacarpophalangeal joints. Two independent methods, (A) the delayed gadolinium enhanced MRI of the cartilage (dGEMRIC, T2-mapping), which was used to assess the biochemical properties of the cartilage; (B) synovitis, osteitis and bone erosions were quantified according to the RA MRI scoring (RAMRIS) method and cartilage thickness (CT), interbone joint space (IBJS, distance between proximal and distal bone surface) and intercartilage joint space (ICJS, distance between proximal and distal cartilage surface) were measured. RESULTS: Biochemical changes of the cartilage, corresponding to low dGEMRIC and high T2 values, were more likely to be seen in joints with decreased IBJS and ICJS as well as decreased CT. For instance, dGEMRIC was directly correlated to the IBJS (p=0.001) and ICJS (p=0.001), whereas T2 mapping was inversely correlated to IBJS and ICJS (both p=0.017). Moreover, the degree of osteitis, and to some extent synovitis, was correlated to biochemical cartilage changes as measured by dGEMRIC (p=0.003) or the T2 mapping (p=0.013). By contrast, bone erosions did not correlate to the degree of biochemical cartilage changes. DISCUSSION: These data support the concept that synovitis and osteitis may be two main triggers for cartilage damage. Thus, the actual inflammatory state of a joint, but not so much the degree of bone erosion, appears to influence cartilage properties in RA.

The Surgical Treatment of a Bimalleolar Ankle Fracture - Tips and Tricks. / Die operative Versorgung einer bimalleolären OSG-Fraktur ­ Tipps und Tricks.

The ankle fracture - the most common fracture of the lower extremities - is usually due to pro- and supination trauma and is commonly challenging for junior doctors of orthopaedics and traumatology. To accomplish sufficient surgical results, it is necessary to have surgical experience, not only because of the surrounding fragile soft tissue, but also due to the specific anatomical structures surrounding the ankle joint and the postsurgical biomechanical stress to osteosynthesis. In the following video, the most relevant steps of surgery as well as some useful tips and tricks are mentioned. The intention of the video is to convey to junior orthopaedic surgeons the most important surgical steps for their clinical daily routine.

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.

Early Changes of the Cortical Micro-Channel System in the Bare Area of the Joints of Patients With Rheumatoid Arthritis.

OBJECTIVE: To characterize the specific structural properties of the erosion-prone bare area of the human joint, and to search for early microstructural changes in this region during rheumatoid arthritis (RA). METHODS: In the initial part of the study, human cadaveric hand joints were examined for exact localization of the bare area of the metacarpal heads, followed by detection of cortical micro-channels (CoMiCs) in this region by high-resolution peripheral quantitative computed tomography (HR-pQCT) and, after anatomic dissection, validation of the presence of CoMiCs by micro-computed tomography (micro-CT). In the second part of the study, the number and distribution of CoMiCs were analyzed in 107 RA patients compared to 105 healthy individuals of similar age and sex distribution. RESULTS: Investigation by HR-pQCT combined with adaptive thresholding allowed the detection of CoMiCs in the bare area of human cadaveric joints. The existence of CoMiCs in the bare area was additionally validated by micro-CT. In healthy individuals, the number of CoMiCs increased with age. RA patients showed significantly more CoMiCs compared to healthy individuals (mean ± SD 112.9 ± 54.7/joint versus 75.2 ± 41.9/joint; P < 0.001), with 20-49-year-old RA patients exhibiting similar numbers of CoMiCs as observed in healthy individuals older than age 65 years. Importantly, CoMiCs were already found in RA patients very early in their disease course, with enrichment in the erosion-prone radial side of the joint. CONCLUSION: CoMiCs represent a new form of structural change in the joints of patients with RA. Although the number of CoMiCs increases with age, RA patients develop CoMiCs much earlier in life, and such changes can even occur at the onset of the disease. CoMiCs therefore represent an interesting new opportunity to assess structural changes in RA.

Age- and Sex-Dependent Changes of Intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis.

The objective of this cross-sectional study was to define normal sex- and age-dependent values of intra-articular bone mass and microstructures in the metacarpal heads of healthy individuals by high-resolution peripheral quantitative computed tomography (HR-pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra-articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR-pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra-articular (intracapsular) bone margins. These data were applied in measuring intra-articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra-articular and radial bone parameters were good (r = 0.51 to 0.62, p < 0.001). In contrast to radial bone, intra-articular bone remained stable until age 60 years (between 297 and 312 mg HA/cm3 ) but decreased significantly (p < 0.001) in women thereafter (237.5 ± 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p < 0.001) loss of intra-articular total (263.0 ± 44.8), trabecular (171.2 ± 35.6), and cortical bone (610.2 ± 62.0) compared with sex- and age-adjusted controls. Standard sex- and age-dependent values for physiological intra-articular bone were defined. Postmenopausal state and RA led to significant decrease of intra-articular bone. © 2016 American Society for Bone and Mineral Research.

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.

Anti­citrullinated protein antibody positivity correlates with cartilage damage and proteoglycan levels in patients with rheumatoid arthritis in the hand joints.

Objective: To investigate the factors associated with cartilage proteoglycan content in patients with rheumatoid arthritis (RA) Methods: 32 RA patients received high-field 3 Tesla Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) for determining cartilage proteoglycan content. Measurements were performed in three individual cartilage regions (medial, central, lateral) of the metacarpophalangeal joints 2 and 3. dGEMRIC values were then related to disease duration, disease activity, anti-citrullinated protein antibody (ACPA) status, rheumatoid factor status and C-reactive protein level. Results: dGEMRIC values were not significantly different between the MCP2 and MCP3 joint. Inter-class correlations were high (>0.92) for all three (medial, central and lateral) cartilage compartments. dGEMRIC values were significantly lower in RA patients with longer disease duration (≥3 years) and those with ACPA positivity than those with a short disease duration (<3 years)(p=0.034) or negative ACPA (p=0.0002), respectively. In contrast, no association between cartilage proteoglycan content and disease activity, C-reactive protein level and rheumatoid factor status was found. Conclusion: Decreased cartilage proteoglycan content in RA patients is associated with disease duration and ACPA positivity but not with the actual disease activity, CRP level or rheumatoid factor status. These data suggest that the cumulative burden of inflammation as well as ACPA are the determinants for cartilage damage in RA.