COPENHAGEN, Denmark—Ischemic heart disease (IHD) accounts for much of the excess cardiovascular (CV) morbidity and mortality in patients with rheumatoid arthritis (RA) and is not entirely explained either by traditional risk factors or by treatment-related side effects. Lone E. Troelsen, MD, and colleagues at the University of Copenhagen, in Denmark, have been examining the possible contribution of various inflammatory mechanisms to heart disease in RA patients. They report in Arthritis & Rheumatism that mannose-binding lectin (MBL) might be part of the problem.¹

RA patients typically have elevated levels of agalactosyl immunoglobulin G (IgG-G0), an altered form of IgG with  oligosaccharide changes in the C2 region that lead to exposure of N-acetylglucosamine. High IgG-G0 levels are associated with poor prognosis in RA, and there is in vitro evidence that the exposed N-acetylglucosamine on IgG-G0 interacts with MBL to activate complement.

"[W]e have shown that genetically determined high levels of MBL confer a substantially increased risk of ischemic heart disease in RA patients and that this association leads to increased risk of myocardial infarction and premature death. Moreover, our results provide, for the first time, in vivo evidence in support of the notion that the presence of complexes of MBL and IgG-G0 represents a significant threat in vivo for RA patients,"  the authors write.

MBL genotypes, 9-year IHD rates studied

The Danish researchers genotyped MBL alleles and measured serum MBL and IgG-G0 levels in 229 patients diagnosed with RA. IHD, myocardial infarction (MI), and death caused by IHD in these RA patients were assessed prospectively. With a median follow-up of 9.54 years, the investigators observed IHD in eight of 27 patients with genetically determined high serum levels of MBL but in only 24 of 192 patients without elevated MBL. Hazard ratios corrected for other known risk factors were 3.6 for IHD, 9.0 for MI, and 10l.5 for death caused by IHD.

Interestingly, these associations were present only in patients with high IgG-G0 levels. "Our observation that high serum levels of MBL conferred increased risk of ischemic heart disease, including myocardial infarction, and death from ischemic heart disease only in patients with high levels of IgG-G0 is in accordance with the hypothesis that complexes of MBL and IgG-G0 are harmful in RA," the authors write. They suggest that MBL/IgG-G0 complexes deposited in the vessel wall could contribute to inflammation-driven atherogenesis.

"It is a possibility, then, that a therapeutic intervention targeted at the products of MBL could be of benefit,"  commented Eric L. Matteson, MD, chair of rheumatology and professor of medicine at the Mayo Clinic College of Medicine, in Rochester, Minnesota. "Prevention of binding of MBL to IgG-GO or interference with IgGO formation, or inhibition of the inflammatory processes set in motion by MBL-IgG-GO might be beneficial in limiting the effects of inflammation induced by this mechanism," Dr. Matteson, who reviewed the MBL study for CIAOMed, added.

However, Dr. Matteson warns that attacking a single target is unlikely to reduce the complex burden of CV disease in RA. He also points out that although the statistical association between MBL and heart disease identified in the Troelsen study has a plausible biological mechanism, it requires further validation before being considered for clinical use. "If the findings are replicated in larger patient groups, and especially if the biology of the putative mechanism is proven and a therapeutic intervention can be developed to address it, then we might see the use of the markers in the clinic," Dr. Matteson said.

Reference

1. Troelsen LN, Garred P, Madsen HO, et al. Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis. Arthritis Rheum. 2007;56:21-29.