Studies on anti-dsDNA Antibodies and other potential biomarkers in Systemic Lupus Erythematosus

Abstract: Systemic Lupus Erythematosus (SLE) is characterized by chronic inflammation involving many organ systems. The etiology is unknown and the pathogenesis has not been fully elucidated. Impairments of the immune system and of the mechanisms regulating cell death are commonly seen in SLE patients. Autoantibodies, in particular anti-dsDNA antibodies, are considered hallmarks of SLE, but the ideal biomarker for SLE is still missing. In this thesis, I summarize the state of the art about biomarkers for SLE and present four original papers, resulting from two different investigations that focused on traditional and novel biomarkers for SLE. The first study concerns the evaluation of anti-dsDNA antibodies as diagnostic and prognostic biomarkers in a realistic clinic scenario. We designed a multicentre study for recruitment and clinical investigation of patients with recent onset of rheumatic symptoms. In paper I, we present the results showing the presence of anti-dsDNA antibodies in many non-SLE patients, with inconsistent results of the assay simultaneously performed in different laboratories. The positivity of the test is found also in about one fourth of ANA negative patients and poses little risk of developing SLE within 5 years, in contrast to previous data. Paper II is a report of results showing that presence of anti-dsDNA antibodies, independently of the assay used, is significantly associated with glomerulonephritis and pleuritis, regardless of the diagnosis. The positivity confirmed by two different methods tends also to cluster with hematological manifestations. We suggest that anti-dsDNA antibodies should be used as biomarkers of certain clinical phenotypes, regardless of the diagnosis. The second part of this thesis concerns the assessment of novel promising biomarkers for SLE. We designed a longitudinal investigation, where patients with established SLE were followed for about two years, with regular clinical and laboratory assessments every other month. I aimed at studying the chronological relationships between the presence of clinical manifestations of SLE and the positivity of the investigated potential biomarkers, namely PNC assay, osteopontin and S100A8/A9. In paper III, the PNC assay is presented as a specific and reliable supplementary laboratory tool in the management of SLE patients. It is a functional test displaying the ability of polymorphonuclear cells to engulf necrotic cell material, which resembles the so-called LE-cell phenomenon. In combination with positivity of other traditional biomarkers, PNC assay may predict important clinical features, herein glomerulonephritis. In paper IV, similar analyses have been performed focusing on osteopontin and S100A8/A9, two pleiotropic proteins that interplay with key mechanisms involved in the pathogenesis of SLE. Their assessment may provide the clinician with important information about the odds of current or upcoming increased disease activity in SLE patients, more specifically clinical features such as arthritis, mucocutaneous manifestations and, above all, glomerulonephritis. The two proteins show weak correlation and low agreement of results, suggesting that their increased levels probably mirror involvement in different pathogenic mechanisms. The results of the present research project contribute to more accurate diagnostic process in patients with recent onset of undiagnosed rheumatic symptoms and more efficient management of patients with established SLE. Being the optimal biomarker still missing, a composite panel of reliable biomarkers may provide the clinician with a tangible support to the clinical acumen.