[Frontiers in Bioscience 9, 1654-1659, May 1, 2004] 1654 SOLUBLE ADHESION MOLECULE LEVELS, NEUROPSYCHIATRIC LUPUS AND LUPUS-RELATED DAMAGE Hayden Zaccagni 1 , Justin Fried 1 , John Cornell 2 , Patricia Padilla 1 and Robin L Brey 1 1 Department of Medicine, Division of Neurology and GRECC, South Texas Veterans Health Care System, Audie L. Murphy Division , VERDICT Center of Excellence, South Texas Veterans Health Care System, Audie L. Murphy Division and the 2 Division of Geriatrics and Gerontology, Department of Medicine, University of Texas Health Science Center at San Antonio TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Methods 3.1. Patient Population 3.2. Serologic Assays 3.3. Statistical Methods 4. Results 5. Discussion 6. Acknowledgements 7. References 1. ABSTRACT Nervous system dysfunction may occur in as many as 80% of patients with Systemic Lupus Erythematous (SLE) at some point in their disease course. Upregulation of adhesion molecules has been linked to acute SLE-related disease activity and chronic damage. We evaluated the relationship between soluble adhesion molecule levels and neuropsychiatric lupus (NPSLE) manifestations using the American College of Rheumatology (ACR) case definitions to investigate for evidence of a link between upregulation of adhesion molecules and NPSLE manifestations. Sera from the initial study visit of 133 SLE patients enrolled in the San Antonio Lupus Study of Neuropsychiatric Disease (SALUD) and 40 controls were evaluated for soluble adhesion molecule levels (VCAM-1, ICAM-1 and E-selectin) and antiphospholipid antibodies. A subset of 57 SLE patients were evaluated for soluble adhesion molecule levels and antiphospholipid antibodies on two subsequent study visits, as well. NPSLE manifestations at the time of sera ascertainment were recorded using ACR case definitions and SLE-related acute activity and damage were measured. Elevated levels of all three soluble adhesion molecules were seen in SLE patients compared to normal control values. Soluble VCAM-1 levels correlated with measures of current disease activity, NPSLE manifestations and deep venous thrombosis. Persistently positive levels of ICAM-1 and VCAM-1, but not E-selectin were association with increased SLE-related damage. Elevated levels of all soluble adhesion molecule levels correlated with abnormal levels of antiphospholipid antibodies, which are associated with some NPSLE manifestations and have been shown to upregulate adhesion molecule expression. 2. INTRODUCTION Neurological dysfunction may occur in as many as 80% of patients with Systemic Lupus Erythematosus (SLE) (1-5). Neuropsychiatric SLE-related (NPSLE) syndromes encompass a wide spectrum of features including strokes, seizures, peripheral neuropathy, dementia, psychosis, anxiety and depression. The American College of Rheumatology (ACR) has published case definitions for nineteen different NPSLE syndromes to help standardize case reporting (6). The etiology of NPSLE manifestations is not well understood, and is likely to be heterogeneous. Medications and toxic or metabolic abnormalities due to systemic organ failure can affect nervous system functioning in patients with SLE (2,3). In addition, a nervous system-directed immune-mediated process can also occur resulting in clinically symptomatic nervous system dysfunction (7-9). Many of these processes also involve abnormal endothelial-white blood cell interactions, which allow proteins or cells access to the central nervous system (CNS). Discovering the factors that regulate endothelial- white blood cell interactions and lymphocyte trafficking into the CNS is of considerable importance in furthering our understanding of NPSLE. The expression of adhesion proteins on endothelial cells appears to up-regulate, and facilitate lymphocyte entry into the CNS in many autoimmune diseases (10-17). Shedding of the active from of these molecules occurs, and soluble levels can be measured in both serum and cerebrospinal fluid (CSF) (18, 19). Although adhesion molecules have been implicated as serological markers in SLE patients with skin disease (20), renal disease (21, 22) and other non-nervous system organ involvement (22-24), few other studies have evaluated soluble adhesion molecule levels in relationship to NPSLE manifestations. 3. METHODS 3.1. Patient Population The patient sample consisted of 133 participants in the San Antonio Lupus Study of Neuropsychiatric