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Objective: Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs)., Methods: We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT., Results: Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02)., Conclusion: We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc., (© 2016, American College of Rheumatology.)

Objective: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort., Methods: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data., Results: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures., Conclusion: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease., (© 2015, American College of Rheumatology.)

This work was undertaken to examine whether human synovium could be engrafted into subcutaneous pouches in the ears of severe combined immunodeficient (SCID) mice. Synovium was transplanted into surgically constructed ear pouches. The grafts were examined by histological and immunohistochemical methods after varying periods after engraftment, or after percutaneous injection of TNF-alpha. Normal, osteo-arthritic and rheumatoid synovium was engrafted successfully in subcutaneous ear pouches. The general morphology and cellular compositions of xenografts were retained including human endothelial cells. In rheumatoid xenografts, macrophages, fibroblasts and lymphocytes persisted for at least 4 weeks. Vascular expression of intercellular adhesion molecule-1 (ICAM-1) was maintained but expression of vascular adhesion molecule-1 (VCAM-1), E-selectin and MHC class II diminished with time. Percutaneous injection of TNF-alpha induced up-regulation of VCAM-1. Human synovium can be engrafted into subcutaneous ear pouches in SCID mice. The xenografts are accessible and respond to injection of a pro-inflammatory cytokine.