Systemic Lupus Erythematosus - Essay Example

SYSTEMIC LUPUS ERYTHEMATOSUS INTRODUCTION Systemic Lupus Erythematosus (SLE), Disseminated lupus erythematosus, Discoid lupus or lupus is a remarkable disease in many aspects; the primary being it is not a single but a protean disease, affecting almost every organ of the body. Second, despite the apparently normal condition of the affected individuals, the disease is fatal and is manifested in form of multiple clinical symptoms associated with other diseases. Finally the disease affects individual of younger ages, who can only be diagnosed up to five years after the appearance of the first set of symptoms (Rahman & Isenberg, 2008), however early diagnosis is the key factor improving prognosis (D’Cruz, 2006). DISEASE DESCRIPTION Pathophysiology SLE is a chronic, inflammatory, prototypic, systemic autoimmune disease affecting connective tissues such as skin, joints along with kidney and serosal membranes. Researches available indicate an environmental cause, which leads to development of the disease in individuals genetically predisposed and therefore vulnerable to it. However, the disease epidemiology is incompletely understood (Rahman & Isenberg, 2008). The disease involves the production of IgG autoantibodies that are specific for self antigens including DNA, nuclear proteins as well as cytoplasmic components. The disease therefore is characterized by inflammation, vasuclitis, vasculopathy. Further, a deposition of the immune complex especially in the renal glomeruli leads to a systemic inflammatory response through activation of complement (C5), or of Fc{gamma}R-mediated neutrophil and macrophages. While the activation of former leads to formation of membrane attack complexes (C5b-9) or anaphylatoxin and cell activator C5a; that of latter causes release of oxidants and proteases; both leading to injury (KEGG, 2009). The mechanism of the disease development has been proposed to involve an abnormal apoptosis followed by elevated levels of cell death and immune intolerance. Cellular antigen redistribution to the cell surface coupled with lymphocytes targeting them leads to injury and inflammation (Andrade et al., 2000). Treatment Diagnosis of SLE is based on the detection of high levels of antinuclear and other antibodies in the blood along with symptoms of SLE. The techniques used for the detection include urinalysis, CBC, ESR, complement levels, ANA (antinuclear antibody test) and other antibody tests, skin and kidney biopsy along with quarterly follow ups. The treatment involves control of disease symptoms and is determined by the severity of the symptoms. Acute SLE involving CNS, cardiovascular and renal diseases are treated with high doses of intravenous steroids and cytotoxic therapy involving corticosteroids, immunosuppresives, antimalarials, and antipsychotic medication (D’Cruz, 2006). Prognosis Early detection is the key factor in improved prognosis of SLE. Prognosis in severe cases too has shown marked improvement during the recent years as a consequence of aggressive treatments available. Common complications associated with SLE include deep vein thrombosis, pulmonary embolism, hemolytic anemia, pericarditis, endocarditis, myocarditis etc (Makover, 2011). Health Disparity SLE exhibits high correlation with women of child bearing age and therefore has been associated with exogenous hormone intake (Costenbader et al., 2007). Lower socioeconomic status further has been linked to higher disease prevalence as well as resultant mortality. Prevalence and Epidemiology The National Arthritis Data Working Group reports that approximately 250,000 Americans have SLE, the worldwide prevalence rates vary with race, being higher in people with African and Asian origins. The disease is more common in the female sex and in individuals within the age group of 20-40yrs. (D’Cruz, 2006). Organizational Description of the Facility The ER, Fast Track, department known as Rapid Medical Screening (RMS) clinic, of the Medical Center of Central Georgia (MCCG), is where I am currently doing my clinical practicum. MCCG is titled a Level I Trauma Center and Magnet™ hospital, aiding the citizens of Central and South Georgia. MCCG’s licensed capacity is 637 beds, comprising of pediatric, obstetric, medical-surgical, intensive care (pediatric, cardiac, neurology, cardiac surgery), and psychiatric. The company serves an appraised population of 750,000 residents and is now the second largest hospital in the state of Georgia. MCCG characteristically treats patients from approximately 80 percent of Georgia’s 159 counties. The mission statement does not directly address SLE, but generally stated, there mission is to provide reasonably priced health care services to the Central and South Georgia community that is comprehensive in range and high-quality. Payment sources for patients include self-pay, indigent, private insurance, Medicaid and Medicare. Technologies used by this clinic to promote safe practice AngioScreen®, MAKOplasty®, SILS™, Endobronchial ultrasound (EBus), superDimension® Electromagnetic Navigation Bronchoscopy system (ENB), and TRU-D™ Rapid Room Sterilization. When it comes to statistical data, no clinical evidence was found to identify the SLE population percentage of using MCCG RMS department. Clinical preceptor, S.B. FNP, stated that it was very rare to actually diagnosis a patient with lupus, without have a long standing rapport and accurate history and physical findings. RMS is commonly used by uninsured patients who may only disclose necessarily what currently is affecting them (MCCG, 2011). CURRENT EVIDENCE-BASED STATUS A recent study conducted by Javierre and colleagues (2010) to study the changes in the pattern of DNA methylation associated with twin discordance in SLE. Monozygotic twins have been reported to be partially concordant for most of the complex diseases including autoimmune disorders. A 100% concordance results due to inheritance of the mutant gene in both of the identical twins indicating that the mutant allele is dominant and highly penetrant. Thus while concordance can be a consequence of heritability, discordance can be employed as a tool for investigation of non-genetic factors. The two major epigenetic factors influencing phenotypic outcomes by regulating gene expression and hence providing alternate pathways of gene function alteration are DNA methylation and histone modification. While epigenetic factors modulate gene functions, they themselves are reportedly dependent on environmental factors such as diet. Alleles identified to be involved in SLE development have been located in the major histocompatibilty complex region, IRFS, STAT4, BLK, BANK1 PDCD1, MECP2, and TNSF4 etc. Most of these genes are also involved in other autoimmune disorders such as rheumatoid arthritis (RA) and dermatomyositis. Besides the genes, epigenetic events such as promoter demethylation of these genes have also been established in lymphocytes of SLE patients. Investigation on monozygotic twins can provide remarkable tool for investigation of epigenetic effects since there is no interference on account of varying DNA sequences including single- nucleotide polymorphisms (SNPs). The study was designed based on the above rationale to investigate the epigenetic factors, specifically DNA methylation pattern in monzygotic twins with discordance for SLE. A group of identical twins discordant for SLE, RA and dermatomyositis; were compared and DNA methylation patterns were studied in them. DNA methylation profiling was conducted using universal bead arrays on 60 DNA samples obtained from the white blood cells of 30 identical twins, along with 30 unrelated age, gender and race matched normal controls. While no differences in DNA methylation patterns were observed in 5 of the twins discordant for RA and dermatomyositis, a difference was observed in SLE discordant 5 identical twins. A common set of genes 49 in number exhibited differential DNA methylation patterns in the SLE affected twin compared to the normal twin. No significant differential methylation was observed in these 49 genes in the five pairs of unrelated normal controls involved in the study. These 49 genes were found to be involved in defense response, cell activation, cell proliferation, immune response and cytokine production. These are the processes affected I the pathogenesis of SLE, providing further evidence of their involvement in SLE. Further the study also investigated the nature of changes brought about in the gene expression as a consequence of altered DNA methylation patterns of the gene promoters. It has been established by prior studies that a global loss in methylation levels can be linked to development of SLE and RA. However, the researchers in this study when attempted to establish the same, by estimating the levels of 5-methylcytosine, found significantly lower levels of DNA methyltransferases (DNMTs), but no changes at Alu, Satellite2, D4Z4 and NBL2 repeats. The study also investigated the three regions of ribosomal RNA gene cluster i.e. the ribosomal gene promoter, 18S and 28S. Significant differences in methylation levels were observed in 18S and 28S regions in the SLE affected twin compared to normal. While the healthy sibling had same levels of methylation as matched controls, the SLE discordant twin exhibited lower levels of methylation in these segments. Though these changes occur downstream to transcription start site, they were observed to increase transcript levels. The significance of use of monozygotic twins for studies involving epigenetic factors was established by this study. The lower levels of methylation of several genes can have important implications in context with prior studies. These studies have reported the association of hypomethylation at key CpGs promoters of genes such as interferon gamma and cytokine genes with lymphocyte activation and differentiation. The study provided the evidence for epigenetic differences in identical twins with discordance of SLE, however whether these differences are responsible for the development of the disease or vice versa could not be established. The study also provided evidence that the epigenetic factors become more pronounced with advancing age. Future Research Major advances in the understanding and treatment of SLE are possible with further research in the field. Despite early diagnosis and improvements in prognosis, the quality of life of SLE patients still remains difficult due to high levels of corticosteroids involved in the treatment procedures, fatigue, infections and cardiovascular risks. Future research should be aimed at development of treatments that can help me better disease management as well as improved prognosis. Clinical trials need to be conducted to evaluate the efficacy of peptides, monoclonal antibodies such as Rituximab and biological agents such as abatacept (CTLA4Ig) and epratuzmab in lupus (D’Cruz, 2006). The Genetic aspects of the disease are as significant as incompletely understood. It is imerative to understand the association fo genes with physiological control of geen responses which become aberrant in SLE. Study of ubiqiutination and methyaltion as mechanisms underlying control of gene expression needs to be further investigated (Rhodes & Vyse, 2008). REFERENCES 1. Andrade, F, L Casciola-Rosen and A. Rosen. "Apoptosis in systemic lupus erythematosus. Clinical implications." Rheum Dis Clin North Am (2000): 215-27. 2. Costenbader, K. H, et al. "Reproductive and menopausal factors and risk of systemic lupus erythematosus in women." Arthritis Rheum (2007): 1251-62. 3. DCruz, D. P. "Systemic lupus erythematosus." BMJ (2006 ): 890-4. 4. Javierre, B. M, A. F Fernandez and J. Richter et al.. "Changes in pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus." Genome Research (2010): 170-9. 5. KEGG. "Systemic lupus erythematosus - Homo sapiens (human)." 2009. GenomeNet. 12 July 2011 . 6. Makover, M. E. "Systemic lupus erythematosus." 2011. PubMed Health. July 2011 . 7. MCCG. About MCCG. 15 June 2011 . 8. Rahman, A and D. A. Isenberg. " Systemic lupus erythematosus." N Engl J Med (2008): 929-39. 9. Rhodes, B and T. J. Vyse. "The genetics of SLE: an update in the light of genome wide association studies." Rheumatology (2008): 1603-11. Read More