Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis
. 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 CX
CR1
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 CX
CR1
mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX
CR1
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.
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.
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).
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.
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.
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.
Objective
To investigate the factors associated with cartilage proteoglycan content in patients with rheumatoid arthritis (RA).
Methods
A total of 32 RA patients received high‐field 3T delayed ...gadolinium‐enhanced magnetic resonance imaging of cartilage (dGEMRIC) to determine cartilage proteoglycan content. Measurements were performed in 3 individual cartilage regions (medial, central, and lateral) of metacarpophalangeal (MCP) joints 2 and 3. T1 dGEMRIC values were then related to disease duration, disease activity, anti–citrullinated protein antibody (ACPA) status, rheumatoid factor (RF) status, and C‐reactive protein (CRP) level.
Results
T1 dGEMRIC values did not differ significantly between MCP joints 2 and 3. Intraclass correlation coefficients were high (>0.92) for all 3 cartilage compartments (medial, central, and lateral). T1 dGEMRIC values were significantly lower in RA patients with longer disease duration (≥3 years) (P = 0.034 for the central compartment) and those with ACPA positivity (P = 0.0002 for the central compartment, P = 0.013 for the lateral compartment). In contrast, no associations were found between cartilage proteoglycan content and disease activity, CRP level, or RF status.
Conclusion
Decreased cartilage proteoglycan content in RA patients is associated with disease duration and ACPA positivity but not with actual disease activity, CRP level, or RF status. These data suggest that the cumulative burden of inflammation as well as ACPAs are the determinants of cartilage damage in RA.
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.
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