Normal growth and development in mice over-expressing the CCN family member WISP3

Loss-of-function mutations in the gene WISP3 cause the autosomal recessive human skeletal disease Progressive Pseudorheumatoid Dysplasia, whereas mice with knockout mutations of Wisp3 have no phenotype. The lack of a phenotype in the Wisp3 knockout mice has constrained studies of the protein’s in vivo function. Over-expression experiments in zebrafish indicated that WISP3 may function as a BMP and Wnt signaling modulator. To determine whether these biologic activities are retained in mice, we created two strains of transgenic mice that over-express WISP3 in a broad array of tissues. Despite strong and persistent protein over-expression, the transgenic mice remained phenotypically indistinguishable from their non-transgenic littermates. Surprisingly, WISP3 contained in conditioned medium recovered from transgenic mouse primary kidney cell cultures was able to bind BMP and to inhibit BMP signaling in vitro. Factors that account for the difference between the in vitro and in vivo activities of WISP3 remain unknown. At present, the mouse remains a challenging model organism in which to explore the biologic function of WISP3

Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Objective. To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. Methods. International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course. Results. A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide. Conclusion. The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols

Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review

To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review

Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome

Objective To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. Study design The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. Results Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. Conclusion The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing