Faculty Bibliography

Sjögren syndrome is a chronic autoimmune disease that typically affects the salivary and lacrimal glands. Aside from the common glandular signs and symptoms, Sjögren syndrome may also cause mononuclear infiltration and immune complex deposition involving extraglandular sites producing several extraglandular manifestations (EGM). The prevalence of EGMs varies greatly depending on the particular manifestation. This article examines the ways that EGMs may present in patients with primary Sjögren syndrome. The focus is on the more prevalent and significant EGMs including involvement of the nervous system, pulmonary manifestations, vasculitis associated with primary Sjögren syndrome, and arthropathy.

Primary Sjögren's syndrome can have multiple extra-glandular manifestations ranging from mild to severe. Treatment for extra-glandular manifestations is organ specific and therapies are targeted based on the primary organs involved. Preferred treatment options used for extra-glandular manifestations of Sjögren's syndrome are usually extrapolated from the physician's experience in treating similar manifestations in other autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematous. The lack of immunomodulating disease modifying drugs in Sjögren's syndrome can be frustrating for patients dealing with extra-glandular manifestations, however recent advances in the field has made the future look promising for new therapeutic options.

Tumor necrosis factor- (TNF-) alpha is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-alpha monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-alpha and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) alpha, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-alpha alone or TNF-alpha with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-alpha significantly reduced both ABCA1 and LXR-alpha mRNA (to 68.5 +/- 1.59%, P < 0.05, and 41.2 +/- 0.25%, P < 0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-alpha effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-alpha. TNF-alpha treatment significantly reduces ABCA1 and LXR-alpha expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes.

Immunologic derangements in rheumatoid arthritis (RA) patients likely contribute to premature atherosclerotic cardiovascular disease (CVD). Traditional CVD risk factors do not reliably identify at-risk RA patients, probably because disease-associated mechanisms are not taken into account. The purpose of this study was to determine whether plasma from subjects with RA exhibits atheroma-promoting properties leading to disruption of cholesterol homeostasis in human monocytes/macrophages. Twenty-one healthy controls (HC) and 22 RA patients were enrolled in an IRB approved study at Winthrop University Hospital. Naive THP-1 macrophages were exposed to plasma from each HC and RA patient. Following incubation, RNA and protein were isolated. QRT-PCR and Western blotting techniques were then used to measure expression of proteins responsible for cholesterol efflux (ATP binding cassette transporter (ABC)A1, ABCG1, 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low density lipoprotein receptor (LOX)-1, CXCL16). To confirm the pro-atherogenic effects of RA plasma on macrophages, foam cell formation was quantified. Results showed that RA plasma downregulates cholesterol efflux proteins and upregulates scavenger receptors CD36, LOX1 and CXCL16. These pro-atherogenic changes in gene expression in the presence of RA plasma are associated with augmented lipid accumulation and foam cell formation by THP-1 macrophages. RA plasma induces macrophage cholesterol overload. Demonstration of disrupted cholesterol homeostasis mediated by RA plasma provides further evidence of the involvement of the immune system in atherogenesis. Our data suggest that chronic exposure to RA plasma adversely affects the capacity of monocytes/macrophages in the arterial wall to metabolize cholesterol and maintain lipid homeostasis, thereby contributing to the development of premature atherosclerosis.