Neuroimmunological and clinical studies in Neuropsychiatric Lupus Erythematosus (NPSLE)
Sammanfattning: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with many organ manifestations and characteristic immunological abnormities including a large set of autoantibodies with affinity for nuclear and membrane components. Autoantibodies form immune complexes, which cause inflammation and tissue damage in affected organs. Neuropsychiatric symptoms in SLE (NPSLE) are common, but clinically we lack a systemic strategy/protocol to follow-up or investigate these patients. Symptoms are heterogeneous, including both central –and peripheral nervous system manifestations. Several cytokines and biomarkers as well as risk factors for NPSLE have been associated with specific manifestations. Especially symptoms of central nervous system origin often contribute to serious clinical outcomes. The overall aim of this thesis was to provide a deeper understanding of NPSLE regarding clinical manifestations, to investigate the performance of potential new biomarkers and possible consequences that may be result from treatment with several immunosuppressive medications. Furthermore, to investigate two of the most common symptoms, stroke and seizures/epilepsy in SLE. In study I, we analyzed whether the activity of the cytokines APRIL and BAFF was enhanced in the systemic and/or the intrathecal compartments in NPSLE patients, as compared to healthy and multiple sclerosis (MS) controls. We also studied the relationship between APRIL/BAFF and fatigue in NPSLE. Levels of APRIL in the intrathecal compartment were significant higher. Fatigue correlated to higher APRIL levels in NPSLE. In study II, plasma and cerebrospinal fluid from NPSLE patients treated with several immunomodulatory medications and controls, were investigated for possible detectable John Cunningham virus (JCV) DNA occurrence. None of these samples showed detectable JCV levels. In study III, we investigated the distribution of ischemic stroke subtypes in SLE patients, and classifying them according the system Trial of Org 10172 in Acute stroke Treatment (TOAST) with possible association with STAT4 and HLA-DRBI risk genotypes. The anti-phospholipid Syndrome (APS) and cardiovascular genes (CE) play important roles in ischemic stroke. Patients with stroke in APS/other determined etiology (OE) were also younger compared with other subgroups. The STAT4 genotype associated specifically to ischemic stroke in both APS/OE and CE subtypes. In study IV, we report that the prevalence of classified seizures and epilepsy in SLE is 11.5%, and the majority of defined epilepsy occurs as a focal epilepsy. APS was more common in patients with epilepsy compared to epilepsy-free SLE patients with or without NPSLE. Cerebrovascular disease was highly significantly more common. In 50% of patients with epilepsy no etiology other than SLE was detected. In conclusion, we have confirmed the importance of cytokines APRIL/BAFF in SLE, also detected in NPSLE in CSF. JCV DNA levels were not detectable in plasma or cerebrospinal fluid for the patients investigated in this study. Furthermore, patients with ischemic stroke seem to have association with APS or CE occurrence. Patients with defined epilepsy in SLE had mostly focal seizures. Cerebrovascular disease is common, and for about half the epilepsy cases we cannot determine any other etiology than autoimmune disease, SLE. Collectively, these findings support the notion of a multifaceted involvement of the nervous system in SLE.
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