Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage

Disease Activity and Chronic Damage. PLoS ONE 7(3): e33824. doi:10.1371/journal.pone.0033824 Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage Guido Valesini 0 Fabrizio Conti 0 Cristiano Alessandri 0 Carlo Perricone 0 Rossana Scrivo 0 Soheila Rezai 0 Fulvia Ceccarelli 0 Francesca Romana Spinelli 0 Elena Ortona 0 Massimo Marianetti 0 Concetta Mina 0 Jerson Laks, Federal University of Rio de Janeiro, Brazil 0 1 Lupus Clinic , Reumatologia , Dipartimento di Medicina Interna e Specialita` Mediche, Sapienza Universita` di Roma , Rome , Italy , 2 Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita` , Rome , Italy , 3 Department of Neurology and ORL, Sapienza Universita` di Roma , Rome , Italy Introduction: Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. Methods: Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-b2-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs). Results: Nineteen percent of patients had mild GCDs impairment (GCDs 2-3), 7% moderate (GCDs 4-5) and 5% severe (GCDs$6). The visuospatial domain was the most compromised (MDZs = 20.8961.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r = 0.331, P = 0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment. Conclusions: Anti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients. - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by frequent neuropsychiatric involvement that could be found up to 80% of patients [17]. Neuropsychiatric SLE (NPSLE) includes a wide range of neurological and psychiatric manifestations as well as cognitive impairment (CI). In 1999, the American College of Rheumatology (ACR) proposed a standard nomenclature for NPSLE with case definitions for nineteen neuropsychiatric syndromes associated with SLE [1]. So far, there is no reliable diagnostic test, which makes the diagnosis of NPSLE difficult. Manifestations of NPSLE vary in severity, ranging from mild headache to lifethreatening coma [8]. Advances in research methodologies and the introduction of neuropsychological methods have improved clinicians ability to identify CI in both pediatric and adult SLE patients [9]. CI in SLE is characterized by deficits in attention, learning and recall, verbal and nonverbal fluency, language, visuospatial skills, executive functions and motor dexterity and is probably due to a damage of fronto-subcortical circuits [46]. The prevalence of CI in SLE patients was found to be comprised between 380% of patients [1014]. This apparent discrepancy is mainly due to the different tests that were administered in these studies, and by the abovementioned only recent application of a specific nomenclature for CI in SLE patients. Petri et al. in 2008 found that after adjusting for age, gender, ethnicity, and education, SLE patients score significantly lower than controls on measures of cognitive efficiency requiring sustained attention/vigilance, visuospatial span of attention/working memory, and simple reaction time [15]. Nonetheless, it was showed that CI in children and adolescents with SLE can affect intelligence, academic achievement, arithmetic, reading comprehension, learning, visual memory and complex problem solving ability [16]. The pathogenesis of NPSLE has been attributed to autoantibody-mediated neuronal dysfunction, vasculopathy, and coagulopathy [1719]. It has been suggested that several autoantibody specificities may play a role in the pathogenesis of NPSLE [reviewed in 20]. Among others, a potential pathogenic relevance has been attributed to anti-neuronal, anti-P ribosomal proteins, anti-phospholipids (aPL), and human N-methyl-D-aspartate (NMDA) receptor types NR2a or NR2b (anti-NR2) antibodies [2029]. Recently, we demonstrated an association between the presence of anti-endothelial-cell antibodies (AECAs) and antiNedd5 C-ter antibodies with psychiatric manifestations, such as psychosis and depression, in SLE [24,25]. In 1999, the ACR Ad Hoc Committee on Neuropsychiatric Lupus nomenclature proposed a brief research battery of neurocognitive tests to quantify cognitive dysfunction in SLE [1]. In 2007 the response criteria for neurocognitive impairment in SLE clinical trials were proposed, and the combination of the ACR neuropsychological battery with the Cognitive Symptoms Inventory (CSI) [30] was suggested to evaluate cognitive function [1,31]. The objective of the present study was to assess cognitive dysfunction in a cohort of Italian SLE patients by using a wide range of neurocognitive tests, including those from the ACR and the CSI, specifically designed to evaluate the fronto-subcortical dysfunction typical of NPSLE. Furthermore, we aimed at testing whether CI in NPSLE was associated with serum autoantibodies, including anti-dsDNA, aPL, AECA, anti-Nedd5, and anti-P ribosomal, and with disease activity and chronic damage. Materials and Methods Fifty-eight consecutive patients $16 years of age affected with SLE, as diagnosed according to the ACR revised criteria [32], were enrolled in this cross-sectional study at the Lupus Clinic, Sapienza University of Rome. Written informed consent was obtained from each patient and the ethic committee of Sapienza Universita` di Roma approved the study design. Study protocol included complete physical examination and blood drawing. The clinical and laboratory data were collected in a standardized computerized electronically-filled form including demographics, past medical (...truncated)