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Summary Macrophages have been described as 'factories' of pro-inflammatory cytokines. Several years ago the present investigators reported that binding of inactive myeloperoxidase (iMPO) to the macrophage-mannose receptor resulted in the induction of TNF and other cytokines. Also, if endothelial cells were incubated with iMPO, but not enzymatically active myeloperoxidase (MPO), upregulation of cytokine mRNA and cytokines was observed. Taken in their entirety, the data suggest a dichotomy of function for myeloperoxidase; that is, enzymatically active MPO functions primarily in cell killing through the 'cytotoxic triad' and iMPO functions as an immunoregulatory molecule through the induction of numerous cytokines. These studies underscore a previously unrecognized interaction among neutrophils, endothelial cells and macrophages, resulting in the induction of TNF and perpetuation of inflammation. The inflammation induced could be relevant in a number of diseases in which neutrophils play a prominent role. The importance of this interaction in the pathogenesis of rheumatoid arthritis is currently under investigation.

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2,447 +/- 61 days (mean +/- standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3 +/- 51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1,476 +/- 63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2,433 +/- 59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86 +/- 1.78, oGA=1.03 +/- 1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.2 7, +/- 0.45 oGA=0.28 +/- 0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66 +/- 0.71, oGA reduced by 0.23 +/- 0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16 +/- 2.52, total enhanced tissue volume=97 +/- 26 microl). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.