BACKGROUND:Crohn’s disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. METHODS: This doubl...BACKGROUND:Crohn’s disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. METHODS: This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti-interleukin-12) in 79 patients with active Crohn’s disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti-interleukin-12 per kilogram of body weight or placebo, with either a four week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primar y end point, and the rates of clinical response (defined by a reduction in the s core for the Crohn’s Disease Activity Index [AI] of at least 100 points) and re mission (defined by a CDAI score of 150 or less) were secondary end points. RESU LTS: Seven weeks of uninterrupted treatment with 3 mg of anti interleukin-12 p er kilogram resulted in higher response rates than did placebo administration (7 5 percent vs. 25 percent, P=0.03). At 18 weeks of follow up, the difference in response rates was no longer significant (69 percent vs. 25 percent, P=0.08). Di fferences in remission rates between the group given 3 mg of anti in terleukin -12 per kilogram and the placebo group in Cohort 2 were not significant at eith er the end of treatment or the end of follow up (38 percent and 0 percent, resp ectively, at both times; P=0.07). There were no significant differences in respo nse rates among the groups in Cohort 1. The rates of adverse events among patien ts receiving anti interleukin-12 were similar to those among patients given pl acebo, except for a higher rate of local reactions at injection sites in the for mer group. Decreases in the secretion of interleukin-12, interferon γ, and tu mor necrosis factor α.by mononuclear cells of the colonic lamina propria accomp anied clinical improvement in patients receiving anti interleukin-12. CONCLUSI ONS:Treatment with a monoclonal antibody against interleukin-12 may induce cli nical responses and remissions in patients with active Crohn’s disease. This tr eatment is associated with decreases in Th1 mediated inflammatory cytokines at the site of disease.展开更多
BACKGROUND: Sargramostim, granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Preliminary studies suggest sargramostim may have act...BACKGROUND: Sargramostim, granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Preliminary studies suggest sargramostim may have activity in Crohn’s d isease. To evaluate this novel therapeutic approach, we conducted a randomized, placebocontrolled trial. METHODS: Using a 2∶1 ratio, we randomly assigned 124 patients with moderatetosevere active Crohns disease to receive 6 μg of sargramostim per kilogram per day or placebo subcutaneously for 56 days. Antibio tics and aminosalicylates were allowed; immunosuppressants and glucocorticoids w ere prohibited. The primary end point was a clinical response, defined by a decr ease from baseline of at least 70 points in the Crohns Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in di sease severity and the healthrelated quality of life and adverse events. RESUL TS: There was no significant difference in the rate of the primary end point of a clinical response defined by a decrease of at least 70 points in the CDAI scor e on day 57 between the sargramostim and placebo groups (54 percent vs. 44 perce nt, P=0.28). However, significantly more patients in the sargramostim group than in the placebo group reached the secondary end points of a clinical response de fined by a decrease from baseline of at least 100 points in the CDAI score on da y 57 (48 percent vs. 26 percent, P=0.01) and of remission, defined by a CDAI sco re of 150 points or less on day 57 (40 percent vs. 19 percent, P=0.01). The rate s of either type o f clinical response and of remission were significantly higher in the sargramost im group than in the placebo group on day 29 of treatment and 30 days after trea tment. The sargramostim group also had significant improvements in the quality o f life. Mildtomoderate injectionsite reactions and bone pain were more com mon in the sargramostim group, and three patients in this group had serious adve rse events possibly or probably related to treatment. CONCLUSIONS: This study wa s negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the qu ality of life in patients with active Crohns disease.展开更多
文摘BACKGROUND:Crohn’s disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. METHODS: This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti-interleukin-12) in 79 patients with active Crohn’s disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti-interleukin-12 per kilogram of body weight or placebo, with either a four week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primar y end point, and the rates of clinical response (defined by a reduction in the s core for the Crohn’s Disease Activity Index [AI] of at least 100 points) and re mission (defined by a CDAI score of 150 or less) were secondary end points. RESU LTS: Seven weeks of uninterrupted treatment with 3 mg of anti interleukin-12 p er kilogram resulted in higher response rates than did placebo administration (7 5 percent vs. 25 percent, P=0.03). At 18 weeks of follow up, the difference in response rates was no longer significant (69 percent vs. 25 percent, P=0.08). Di fferences in remission rates between the group given 3 mg of anti in terleukin -12 per kilogram and the placebo group in Cohort 2 were not significant at eith er the end of treatment or the end of follow up (38 percent and 0 percent, resp ectively, at both times; P=0.07). There were no significant differences in respo nse rates among the groups in Cohort 1. The rates of adverse events among patien ts receiving anti interleukin-12 were similar to those among patients given pl acebo, except for a higher rate of local reactions at injection sites in the for mer group. Decreases in the secretion of interleukin-12, interferon γ, and tu mor necrosis factor α.by mononuclear cells of the colonic lamina propria accomp anied clinical improvement in patients receiving anti interleukin-12. CONCLUSI ONS:Treatment with a monoclonal antibody against interleukin-12 may induce cli nical responses and remissions in patients with active Crohn’s disease. This tr eatment is associated with decreases in Th1 mediated inflammatory cytokines at the site of disease.
文摘BACKGROUND: Sargramostim, granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Preliminary studies suggest sargramostim may have activity in Crohn’s d isease. To evaluate this novel therapeutic approach, we conducted a randomized, placebocontrolled trial. METHODS: Using a 2∶1 ratio, we randomly assigned 124 patients with moderatetosevere active Crohns disease to receive 6 μg of sargramostim per kilogram per day or placebo subcutaneously for 56 days. Antibio tics and aminosalicylates were allowed; immunosuppressants and glucocorticoids w ere prohibited. The primary end point was a clinical response, defined by a decr ease from baseline of at least 70 points in the Crohns Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in di sease severity and the healthrelated quality of life and adverse events. RESUL TS: There was no significant difference in the rate of the primary end point of a clinical response defined by a decrease of at least 70 points in the CDAI scor e on day 57 between the sargramostim and placebo groups (54 percent vs. 44 perce nt, P=0.28). However, significantly more patients in the sargramostim group than in the placebo group reached the secondary end points of a clinical response de fined by a decrease from baseline of at least 100 points in the CDAI score on da y 57 (48 percent vs. 26 percent, P=0.01) and of remission, defined by a CDAI sco re of 150 points or less on day 57 (40 percent vs. 19 percent, P=0.01). The rate s of either type o f clinical response and of remission were significantly higher in the sargramost im group than in the placebo group on day 29 of treatment and 30 days after trea tment. The sargramostim group also had significant improvements in the quality o f life. Mildtomoderate injectionsite reactions and bone pain were more com mon in the sargramostim group, and three patients in this group had serious adve rse events possibly or probably related to treatment. CONCLUSIONS: This study wa s negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the qu ality of life in patients with active Crohns disease.
