Purpose: Crohn's disease is associated with impaired HRQOL. This analysis investigated HRQOL outcomes during maintenance therapy with natalizumab (a humanized monoclonal IgG4 antibody to α4 integrin) in the ENACT-2 trial where higher rates of sustained response and remission were observed compared with placebo. Methods: Patients who responded to natalizumab induction therapy (n = 339) were randomized to natalizumab 300 mg (n = 168) or placebo infusions (n = 171) given monthly for up to 12 months. HRQOL was measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Short Form-36 (SF-36) at months 0, 3, 6, 9, and 12. Higher scores indicate better HRQOL. A minimally important difference (MID) is defined as 16 pts for Total IBDQ and 5 pts for SF-36 summary scores. Results: The change for all IBDQ scales from ENACT-1 baseline was significantly greater (p < 0.05) in natalizumab-treated patients at all timepoints. Changes in 7 of 10 SF-36 scales were significant by month 3 and all were significant in months 9 and 12. A significantly greater proportion of natalizumab patients achieved MID on the Total IBDQ at months 6–12 and the SF-36 PCS at months 3–12. Mean scores for physical function, social function, role-emotional, and mental health approximated US norms at month 12. Conclusions: Maintenance therapy with natalizumab resulted in significantly improved HRQOL, as evidenced by both disease specific (IBDQ) and general (SF-36) measures.Table: Change From Baseline [Mean (SD)]
Abstract The pathways leading to activation of mucosal lamina propria (LP) T cells differ from those of peripheral T cells. LP T cells exhibit enhanced IFN‐γ secretion when activated through the CD2 pathway. This study demonstrates CD2 signaling is followed by activation of STAT proteins in both peripheral blood mononuclear cells (PBMC) and lamina propria mononuclear cells (LPMC), although, distinct differences exist in regulation of IFN‐γ promoter gene expression. Both PBMC and LPMC exhibit enhanced secretion and transactivation of the –2.7 kb IFN‐γ promoter region following CD2 signaling, but the IFN‐γ STAT‐binding region (within the first intron) serves as an orientation‐independent enhancer of promoter activity only in LPMC. Mutation of the STAT site impairs enhancer activity. In LPMC, but not PBMC, CD2 mediates binding of STAT1 and STAT4 to the IFN‐γ intronic element. Unstimulated LMPC exhibit low levels of phosphotyrosine‐STAT4 and STAT1 and phosphoserine‐STAT1, which increase substantially following CD2 activation. In PBMC, CD2‐mediated phosphorylation is primarily restricted to enhanced levels of phosphotyrosine‐STAT1. Thus, these results indicate that both common as well as unique molecular mechanisms are involved in CD2 signaling and activation of the STAT pathway in LP T cells which are critical for regulation of IFN‐γ expression in the gut.
