Engineering a DNA damage response without DNA damage

Recent work has achieved the feat of activating the DNA damage checkpoint in the absence of DNA damage, revealing the importance of protein-chromatin associations for the activation, amplification and maintenance of the DNA damage response.     

Joint damage in rheumatoid arthritis: assessment of a new scoring method

Introduction

The aim of this study was to assess a novel approach for the quantification of finger joint space narrowing and joint destruction in patients with rheumatoid arthritis (RA) focusing on the peripheral hand articulations.

Methods

A total of 280 patients with verified RA underwent computerized semi-automated measurements of joint space distance at the finger articulations based on radiographs. The Z-Score, which can differentiate between joint space alterations caused by RA versus age/gender-related changes, was calculated as a comparative parameter. The severity of joint space narrowing was also quantified by the Sharp Score. Sensitivity and specificity of the Z-Score (based on joint space widths differentiated for each peripheral finger joint) were evaluated to reveal the potential for the occurrence of erosions. Additionally, the potential of the Z-Score regarding the differentiation of therapeutic effects on joint space widths in patients under a therapy of methotrexate versus leflunomide was performed.

Results

The Z-Scores of finger articulations in patients with RA were generally decreased. Metacarpal-phalangeal (MCP) joint articulations showed a continuous significant decline of -1.65 ± 0.30 standard deviations dependent on the Sharp Score. The proximal-interphalangeal joints also revealed a significant reduction of the Z-Score (-0.96 ± 0.31 standard deviations). The sensitivity and specificity of MCP joint space distance for the detection of erosions were 85.4% versus 55.2%. The Sharp Score for joint space narrowing was not able to detect different treatments, whereas an accentuated stabilization of joint space narrowing could be identified for the Z-Score of the MCP joints in patients treated with leflunomide and methotrexate.

Conclusion

The Z-Scoring method based on computer-aided analysis of joint space widths was able to reliably quantify severity-dependent joint space narrowing in RA patients. In the future, calculation of a Z-Score based on gender-specific and age-specific reference data shows the potential for a surrogate marker of RA progression that comprehends the early identification of patients with RA, and in particular those with erosive course of the disease, enabling a timely therapeutic strategy for cartilage protection.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation leading to cartilage destruction and resulting in joint space narrowing, bone erosions, and periarticular demineralization. Consequently, RA scoring from radiographs involves three aspects: bone mineral density, joint space width, and hand erosion count. Besides the measurement of disease activity, a major outcome criterion of clinical trials is the assessment of radiographic progression based on the detection of erosions and joint space narrowing [1]. However, currently established scoring methods, although widely applied, have been associated with several limitations such as limited generalizability and objectivity due to the difficulty of standardized scoring by different readers with variable experience [2].Recent advances in computer-aided diagnosis now offer the opportunity for a standardized measurement of radiographically visible alterations focusing on the small joints of the hand [3], with a focus on the assessment of joint space widths [4]. Computer-based methods for the measurement of joint space width could provide substantial advantages in comparison with the assessment of joint space narrowing by manual scoring methods, because of improved standardization, sensitivity, and reproducibility [5,6].Computer-aided joint space analysis (CAJSA) is a relatively new technique that performs semi-automated measurements of joint space distances (JSDs) at the finger articulations using digitized hand radiographs [7]. Recently, new data have shown an age-specific and gender-specific joint space narrowing in healthy subjects and RA patients [7,8].Pfeil and colleagues introduced the Z-Score to differentiate RA-induced joint space narrowing from age-related and gender-related changes of finger joint space widths [9]. The aim of this study was to assess the potential of this novel approach based on Z-Score calculations to reliably quantify finger joint space narrowing in RA patients as well as to illustrate its sensitivity and specificity depending on the occurrence of bone erosions. Additionally, the clinical relevance of the Z-Score was determined in the comparison of two different patient groups treated with methotrexate and leflunomide considering a head-to-head comparison of manual and automated joint space narrowing scoring.     

Autoimmunity: Another pathway towards arthritis.

A new pathway leading to arthritis has been revealed by the discovery that antibodies specific for a ubiquitously expressed antigen are able to transfer a severe arthritic phenotype in mice. This new model will be useful for further analyses of the different pathways involved in rheumatoid arthritis.     

Autoimmunity and hypothyroidism

Primary myxedema and hypothyroid Hashimoto's disease provide a well-documented example of organ-specific autoimmunity in man. Very slight modifications or increased release of thyroglobulin or thyroid antigens in the circulation may cause the rupture of autotolerance for the normal thyroid components, at least when individuals have a genetic predisposition to autoimmune thyroiditis (possibly associated with a predisposition to other autoimmune diseases). The demonstration of an association between HLA and thyroiditis, however, requires additional studies. The basic immunological abnormality responsible for autoimmunization against thyroid components is a defect in suppressor T cells, shown in experimental animals but not firmly established in man. The result of autoimmunization will be the appearance of cytotoxic mechanisms that lead to destruction of the thyroid follicle with progressive fibrosis, antibody-dependent cell-mediated cytotoxicity apparently being of major importance. A recent report shows, in addition, that thyroid atrophy in primary hypothyroidism is associated with the production of antibodies that block the thyroid-growth-promoting activity of TSH. The recent progress made in our understanding of autoimmune thyroiditis will certainly contribute to improving our knowledge of how and when autoimmunization might develop in man.