Decreased use of non-steroidal anti-inflammatory drugs for the treatment of juvenile idiopathic arthritis in the era of modern aggressive treatment.

We examined whether the use of non-steroidal anti-inflammatory drugs has decreased for the treatment of juvenile idiopathic arthritis in a cohort treated with aggressive modern therapy as well as potential factors influencing their use. We randomly sampled 100 of 377 patients with juvenile idiopathic arthritis treated by pediatric rheumatologists at our center between 2003 and 2008. We used electronic health records and detailed chart review to examine the trends of non-steroidal anti-inflammatory drug use and factors impacting use, including disease subtype, disease activity, adverse effects, and other medication use. Data were analyzed longitudinally using a non-linear mixed effects regression model. Ninety-two percent used non-steroidal anti-inflammatory drugs at some point and 70% at anti-inflammatory doses. At patients' last visit within the study time frame, 52% were using non-steroidal anti-inflammatory drugs and only 28% at anti-inflammatory doses, decreased from 79 and 56%, respectively, at their first visit. In 2003, 53% used an anti-inflammatory dose compared to 35% in 2008. Active joint count was significantly associated with non-steroidal anti-inflammatory drug use at anti-inflammatory doses, while methotrexate and biologic modifiers use, later calendar year, the presence of uveitis, and positive anti-nuclear antibody status were significant negative predictors. The use of non-steroidal anti-inflammatory drugs decreased significantly over time, with decreasing numbers of active joints, and when methotrexate or biologic modifiers were used. The number of patients currently using non-steroidal anti-inflammatory drugs is less than reported in series from the 1990s.

alpha4 Integrin/FN-CS1 mediated leukocyte adhesion to brain microvascular endothelial cells under flow conditions.

Insights into sequential leukocyte-endothelial interactions during leukocyte trafficking have been obtained through experiments using human umbilical vein endothelial cells (HUVEC) under flow conditions. To investigate leukocyte-brain endothelial cell interactions, we developed a dynamic in vitro system, using Transfected Human Brain Microvascular Endothelial Cells (THBMEC) and a parallel plate flow chamber. Human peripheral blood mononuclear cells (PBMC) were perfused across confluent THBMEC cultures at a velocity that approximates the rate found in human brain capillaries. Leukocyte-THBMEC interactions were visualized by phase-contrast microscopy, and images were captured on a CCD camera. To simulate inflammatory conditions, we activated THBMEC with the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), which up-regulated chemokine and adhesion molecule expression in THBMEC without affecting the distribution of immunoreactivity for tight junction-associated proteins. PBMC adhesion was enhanced by cytokine-mediated activation of THBMEC. G protein-coupled receptor (GPCR) activation was essential for leukocyte-THBMEC interaction, as pertussis toxin (PTX) treatment of PBMC abrogated PBMC adhesion to activated THBMEC. The anti-alpha4 integrin antibody, natalizumab, infused into MS patients, significantly reduced the adhesion of their ex vivo PBMC to activated THBMEC under flow conditions. Further study showed that alternatively spliced fibronectin containing the CS1 region (FN-CS1), but not Vascular Cell Adhesion Molecule type 1 (VCAM-1), was the ligand of alpha4 integrin on activated THBMEC. Blocking FN-CS1 abrogated PBMC adhesion on activated THBMEC, while anti-VCAM-1 antibodies had no effect. These results established a novel in vitro dynamic BBB model. We also demonstrated the dependence of leukocyte-endothelial interactions in this model on alpha4 integrins and FN-CS1.