Sargramostim for active Crohn's disease.

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 disease. To evaluate this novel therapeutic approach, we conducted a randomized, placebo-controlled trial. METHODS: Using a 2:1 ratio, we randomly assigned 124 patients with moderate-to-severe active Crohn's disease to receive 6 mug of sargramostim per kilogram per day or placebo subcutaneously for 56 days. Antibiotics and aminosalicylates were allowed; immunosuppressants and glucocorticoids were prohibited. The primary end point was a clinical response, defined by a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in disease severity and the health-related quality of life and adverse events. RESULTS: 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 score on day 57 between the sargramostim and placebo groups (54 percent vs. 44 percent, 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 defined by a decrease from baseline of at least 100 points in the CDAI score on day 57 (48 percent vs. 26 percent, P=0.01) and of remission, defined by a CDAI score of 150 points or less on day 57 (40 percent vs. 19 percent, P=0.01). The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment. The sargramostim group also had significant improvements in the quality of life. Mild-to-moderate injection-site reactions and bone pain were more common in the sargramostim group, and three patients in this group had serious adverse events possibly or probably related to treatment. CONCLUSIONS: This study was negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease.

Granulocyte-macrophage colony-stimulating factor induces modest increases in plasma human immunodeficiency virus (HIV) type 1 RNA levels and CD4+ lymphocyte counts in patients with uncontrolled HIV infection.

BACKGROUND: Studies have reported that plasma human immunodeficiency virus type 1 (HIV-1) RNA levels and CD4+ lymphocyte counts in HIV-infected patients improved after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: In AIDS Clinical Trials Group Protocol 5041, 116 patients were enrolled in a double-blind, randomized, placebo-controlled clinical trial of 16 weeks of 250 microg of GM-CSF administered subcutaneously 3 times/week, followed by open-label treatment for an additional 32 weeks. Patients had stable baseline plasma HIV-1 RNA levels of > or =1500 copies/mL and received constant antiretroviral regimens through at least the first 16 weeks of the study. RESULTS: After 16 weeks, the GM-CSF group tended to have greater, though clinically insignificant, increases in plasma HIV-1 RNA levels, compared with the placebo group (median change, +0.048 vs. -0.103 log copies/mL; P=.036, in a post hoc analysis). There were trends toward progressive modest increases in CD4+ lymphocyte counts with GM-CSF treatment at 16 weeks (median change, +14 vs. -6 cells/mm3; P=.06) and beyond. CONCLUSIONS: GM-CSF does not have an antiviral effect in patients with ongoing HIV replication but may increase CD4+ lymphocyte counts.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) restores allostimulatory function to accessory cells in patients with AIDS.

BACKGROUND: Impaired allostimulatory function of dendritic cells in patients with AIDS has been reported previously. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can restore the T-cell stimulatory function in transforming growth factor-beta 1 (TGF-beta 1)-inhibited murine accessory cells. We now report the effect of intravenous recombinant human GM-CSF (rhGM-CSF) on accessory cells of HIV-infected patients. METHOD: The in vivo effect of GM-CSF on allostimulatory function of accessory cells was evaluated. Seventeen individuals with AIDS received a single infusion of rhGM-CSF (125 mg/m(2) over 120 minutes). Samples of peripheral blood lymphocytes (PBL) were taken at 1, 5, and 24 hours after infusion, and the allostimulatory capacity was measured. RESULTS: A single bolus infusion of rhGM-CSF resulted in significantly increased accessory cell function in 13/17 (88%) patients at one or more assayed time points after infusion. CONCLUSION: These results suggest that the administration of rhGM-CSF can potentially restore allostimulatory function to accessory cells in HIV-infected patients, and this presents a novel way of immune reconstitution. Clinical significance of this approach of immune reconstitution in AIDS patients warrants further investigations.