Systemic Lupus Erythematosus Disease

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Table of Contents

Introduction
Epidemiology of systemic lupus erythematosus (volume of the problem)
Etiology and Risk factors
Pathogenesis of systemic lupus erythematosus
Pathology of systemic lupus erythematosus (anatomical changes)
Other organs (Lungs, nervous system, and GIT)
Conclusion
Works Cited

Introduction

Systemic lupus erythematosus (SLE) is a chronic, complex autoimmune disease characterized by high levels of non-organ specific, self-reactive antibody production leading to immune complex formation. A disease characteristic is a remission and relapse, and its etiology remains indefinable. The disease results in multiple health problems including increased infection, renal and skin disorders, neurological complications, osteoporosis, rheumatoid arthritis, osteoarthritis, and fibromyalgia. Tissue damage associated with a severe injury can result in marked immune dysfunction that involves suppressive cell types and a cascade of inflammatory and tissue reparative mediators (Anam et al 106).

The essay aims at providing a brief yet comprehensive review focusing on the etiology and risk factors of SLE, pathogenesis, pathophysiology, and organ changes secondary to the disease.

Epidemiology of systemic lupus erythematosus (volume of the problem)

For a disease characterized by remissions and relapses determination of both incidence (new cases) and prevalence (existing cases) may be difficult especially in observational studies (Joseph et al 1814). Current evidence suggests geographical, ethnic, gender, and age differences in incidence, in the USA, the incidence is 6-35 in 10000 population, while in the UK, it is 200 in 100.000 (Somers et al, 615). Mortality has significantly decreased during the past 50 years from 50% at 5 years to 15% at 10 years.

However, recent studies (Europe and Canada) show increased mortality with longer disease duration with atherosclerosis, myocardial infarction, nephritis, infection, pneumonitis, and pulmonary hypertension as leading causes of death (Abu-Shakra1906). About ethnic differences, the disease is more common in African-Americans, Asian Indians (in the UK), and Asians. It is more common in adults, old age, and children females (10-15:1, 8:1, and 3:1 respectively) with 65% of patients having the disease onset between 16 to 55 years (Jimenez et al 33).

Etiology and Risk factors

The cause of SLE remains unknown, although many observations suggest a role for genetic, hormonal, immune, and environmental factors. The evidence for hormonal abnormalities is based primarily on the observation that SLE is much more common among women in their childbearing years. In addition, SLE has been observed in some males with Klinefelter’s syndrome, and some abnormalities of estrogen metabolism have been noted in both men and women with SLE. Immune abnormalities occur in patients with SLE, the etiology of which remains unclear; also there is a lack of evidence on which are primary and which are secondary.

Some of these immune defects are episodic, and some correlate with disease activity. SLE is primarily a disease with abnormalities of immune regulation. These abnormalities are thought to be secondary to a loss of self-tolerance; that is, SLE patients (either before or during disease evolution) are no longer tolerant of all their self-antigens and thus an immune response develops to these antigens. The number of suppressor T cells also decreases; these would normally be down-regulating (maintaining homeostasis) immune responses (Schur 1588).

Some genetic marker associations are found more frequently in SLE patients of different races and ethnicities. It has been calculated that at least four genes are involved in predisposing individuals to SLE. Each gene presumably affects some aspect of immune regulation, protein degradation, and peptide transport across cell membranes, immune response, complement, the reticuloendothelial system (including phagocytosis), immunoglobulins, apoptosis, and sex hormones. Thus combinations of dissimilar gene defects may result in distinct abnormal responses and produce separate pathologic processes and different clinical expressions (Harley et al 288).

Cojocaru et al (2008 p. 122) suggested environmental factors play a role in triggering autoimmune diseases, then multiple interactions between genetic and environmental factors become responsible for the autoimmune processes. Shoenfeld et al (2008 p. 8) pointed to some of the environmental factors, first, the circadian changes in metabolism and hormonal levels can be responsible for the diurnal variations in the immune response and related clinical symptoms. Second Epstein Barr virus infection can trigger the immune reaction either by mimicry to a self-antigen or by activating the local reaction of the antigen-presenting cells. Since SLE is commoner during pregnancy, hormonal level disturbances can be one of the environmental factors. Finally, studies showed physical and psychological stress and smoking are significant environmental factors that trigger autoimmune mechanisms.

Pathogenesis of systemic lupus erythematosus

No single abnormality of the immune system is the sole cause of systemic lupus erythematosus. The pathogenesis of the disease depends on the interplay of a number of different factors. These include auto-antibodies, T lymphocytes, cytokines, the complement system, and apoptosis (Rahman and Isenberg 6341).

B lymphocytes and auto-antibodies

Auto-antibodies are those which bind to antigens present within the tissues of the body itself. Antibodies to double-stranded DNA (anti-dsDNA) have been cited widely as possible causative agents in systemic lupus erythematosus, particularly in lupus glomerulonephritis. Levels of these antibodies rise and fall with disease activity in systemic lupus erythematosus; thus, their titer is a useful indicator for disease activity. Deposits of anti-dsDNA occur in the glomeruli of patients with lupus nephritis with associated proteinuria. This process is dependent on help from T cells; nucleosomes derived from cell apoptosis are likely to be involved, although a role for viral DNA binding proteins has also been suggested. The pathogenic potential of autoantibodies in systemic lupus erythematosus (particularly IgG anti-dsDNA) rests upon their ability to deposit in tissues like the kidney and skin and to activate complement (Rahman and Isenberg 6343).

Anti-phospholipid antibodies

The origin of these antibodies is similar to that of anti-dsDNA antibodies, the antigen, in this case, maybe phosphatidylserine on the outer surfaces of blebs derived from apoptotic cells. The pathological effects of anti-phospholipid antibodies are not due to deposition and complement activation but to the promotion of thrombus formation (Rahman and Isenberg 6344).

T lymphocytes

Since the process of antigen-driven selection of mutations in B lymphocytes is dependent on help from helper T lymphocytes, therefore, antigen-specific T cells might also contribute to the pathogenesis of the disease. Patients with systemic lupus erythematosus have decreased levels of the subset of T cells carrying the CD4 and CD45Ro surface markers, which may be involved in the stimulation of suppressor T lymphocytes. Thus, suppression becomes insufficient to prevent the production and survival of auto-reactive B-lymphocyte and helper T-lymphocyte clones (Rahman and Isenberg 6346).

Apoptosis and complement

Apoptosis leads to the production of surface blebs of cellular material that include a number of the antigens to which auto-antibodies develop. A deficiency in the clearance of products of apoptosis allows producing a wide spectrum of auto-antibodies, the reason may be defective monocyte’s phagocytic function, or since this process is complement-dependent, complement deficiencies (Mok and Lau 486).

The role of cytokines

Cytokines enhance the ability of cells to interact and are therefore important in T- and B-cell functions abnormalities seen in patients with lupus. The balance between cytokines from the T1 Helper cells and T2 Helper cells (TH1 and TH2 cells) is essential in determining the outcome of the immune response. Lupus might be expected to be a disease in which TH2 cells predominate, resulting in excessive help for B cells and overproduction of antibodies.

In support of this notion, increased levels of IL-10 have been found in patients with lupus. This cytokine suppresses TH1 cells and thus impairs cell-mediated immunity, a characteristic feature of the disease. Accessory cells in lupus seem to produce insufficient amounts of IL-1 and IL-2 to provide the necessary activation signals for T cells, this reduction is likely to have a significant effect on T-cell responses (Mok and Lau 485).

Pathology of systemic lupus erythematosus (anatomical changes)

The main pathological changes in the organs of patients with SLE are inflammation, vasculitis, immune complex deposition, and vasculopathy (Mok and Lau 481).

The skin

It is the primary target organ (85% of cases); the diagnostic lesion is erythema, in a butterfly distribution on the cheeks of the face and across the bridge of the nose (malar flush) is characteristic. Vasculitic lesions on the fingertips and around the nail folds, purpura and urticaria occur. In 40–50% of cases, there is photosensitivity where prolonged exposure to sunlight can lead to exacerbations of the disease. The induction of skin lesions of SLE by ultraviolet light combined with alterations in adhesion molecules contribute to the accumulation of inflammatory cells in this disease. Palmar and plantar rashes, pigmentation, and alopecia are distressing especially for females. Raynaud’s phenomenon is common and may precede the development of other clinical problems over years. Discoid lupus (commonest from) is a benign variant of lupus in which only the skin is involved. The rash is characteristic and progresses to scarring and pigmentation (Kuhn and Ruzicka 6).

Cardiovascular system

Cardiac involvement in patients with systemic lupus erythematosus may include pericarditis, characterized by a positive antinuclear antibody in the pericardial fluid, myocarditis, valvulopathy, coronary Libman-Sacks endocarditis, which is non-infective vegetation that may be present in up to 50% of patients with systemic lupus erythematosus. It does not embolize or disturb valvular function. Further, inflammation and fibrosis of the conduction system may lead to heart block (Klarich and Behrenbeck p 59).

The kidneys

Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with SLE. Approximately 25% of patients with SLE have substantial renal involvement. If renal involvement occurs with SLE, it is usually early in the course of the disease, but rarely is renal involvement the sole manifestation of SLE. LN is more severe in children and African-Americans. The patterns of LN are not static and may show a transition from one class to another either spontaneously or after treatment. Renal affection may take the form of necrotizing glomerulonephritis with crescents, with glomerular deposition of IgG, IgM, IgA, complements C1q, and C4.

Immune deposits are localized to the glomerular capillary subendothelium (wire-loop) and a fingerprint-like pattern of tubuloreticular inclusions is common within glomerular and vascular endothelial cells. Membranous LN is characterized by proteinuria, weakly positive or negative antinuclear antibody, and no erythrocyte casts. Other manifestations of SLE include acute and chronic tubulointerstitial nephritis and glomerular capillary thrombi in patients with anti-phospholipid antibodies (Fervenza and Schwab 577-578).

Other organs (Lungs, nervous system, and GIT)

Up to 50% of patients will have lung involvement sometime during the disease. Recurrent pleurisy and pleural effusions (exudates) are the most common manifestations and are often bilateral. Pneumonitis and atelectasis may be seen; eventually, a restrictive lung defect develops with loss of lung volumes and raised hemi-diaphragms. Intrapulmonary hemorrhage associated with vasculitis is a rare but potentially life-threatening complication. Involvement of the nervous system occurs in up to 60% of cases and symptoms often fluctuate. There may be a mild depression but occasionally more severe psychiatric disturbances occur.

Epilepsy, migraines, cerebellar ataxia, aseptic meningitis, cranial nerve lesions, cerebrovascular disease, or polyneuropathy may be seen. The pathogenic mechanism for cerebral lupus is complex. Lesions may be due to vasculitis or immune-complex deposition, thrombosis, or non-inflammatory microvasculopathy. The commonest finding on MRI scans is of increased white matter signal abnormality. About the GIT, mouth ulcers are common and may be a presenting feature. These may be painless or become secondarily infected and painful. Mesenteric vasculitis can produce inflammatory lesions, infarction, or perforation involving the small bowel (Shipley et al 541-542).

Conclusion

To wrap up the previous discussion, essential for the diagnosis of SLE are a young female patient in the childbearing period (commonest) with malar rash, joint pains, multiple system affection, anemia, thrombocytopenia, and neutropenia. Serological tests show anti-dsDNA and antinuclear antibodies, and low serum complement, especially during disease relapses. Despite advances in understanding the pathogenesis of SLE, it represents a significant risk of mortality and chronic morbidity.

Works Cited

Abu-Shakra, M. “Do Improved Survival Rates of Patients with Systemic Lupus Erythematosus Reflect a Global Trend?” The Journal of Rheumatology 35(10), (2008): 1906-1908.

Anam, K., Amare, M., Naik, S., et al. “Severe Tissue Trauma Triggers Lupus Autoimmune Disease”. Progress in Systemic Lupus Erythematosus Research. Ed. Seward, T. L. New York: Nova Biomedical Books, 2007.

Cojocaru, M., Mihaela, I., and Silosi, I. “Autoimmune diseases and their environmental triggers.” Maedica 3(2) (2008): 122-127.

Fervenza, F. C., and Schwab, T. R. “Nephrology: Part 1”. Mayo Clinic Internal Medicine: Concise Textbook. Ed. Habermann, T. M., and Ghosh, A. K. Rochester, MN: Mayo Clinic Scientific Press, 2008.

Harley, I. T. W., Kaufman, K. M., Langefeld, C. D., et al. “Genetic Susceptibility to Lupus: New Insights from mapping and genome-wide associations studies.” Nat Rev Genet 10(5), (2009): 285-290.

Jimenez, S., Cervera, R., Ingelmo, M., et al. “The Epidemiology of Lupus Erythematosus”. Cutaneous Lupus Erythematosus. Ed. Kuhn, A., Lehmann, P., and Ruzicka, T. Heidelberg: Springer, 2005.

Joseph, S. B., Pineau, C. A., Tamblyn, R. et al. “A population-based assessment of systemic lupus erythematosus incidence and prevalence-results and implications of using administrative data for epidemiological studies.” Rheumatology 46, (2007): 1814-1818.

Klarich, K. W., and Behrenbek, T. “Cardiology: Part 1 (Chapter 3)”. Mayo Clinic Internal Medicine: Concise Textbook. Ed. Habermann, T. M., and Ghosh, A. K. Rochester, MN: Mayo Clinic Scientific Press, 2008.

Kuhn, A., and Lehmann, P. Cutaneous Lupus Erythematosus. Dusseldorf, Germany: Springer, 2005.

Mok, C. C., and Lau, C. S. “Pathogenesis of systemic lupus erythematosus.” J Clin Pathol 56 (2003): 481-490.

Rahman, A., and Isenberg, D. “Systemic lupus erythematosus and related disorders (Chapter 18.10.2)”. Oxford Textbook of Medicine (4th edition). Ed. Benz, E. J. JR., Cox, T. M., and Firth J. D. New York: Oxdord University Press, USA, 2003.

Schur, P. H. “Systemic Lupus Erythematosus (Chapter 289)”. Cecil Textbook of Medicine (21st edition). Ed. Ausiello, D. A., and Goldman, L. St. Louis: Saunders, 2007.

Shipley, M., Rahman, A., O’Gradaigh, D. et al. “Rheumatology and bone disease”. Kumar & Clark’s Clinical Medicine (7th edition). Ed. Kumar, P., and Clark, M. London: Saunders, 2009.

Shoenfeld, Y., Zandman-Goddard, G., Stojanovich, L., et al. “The Mosaic of Autoimmunity: Hormonal and Environmental Factors Involved in Autoimmune Diseases-2008.” IMAJ 10, (2008): 8-12.

Somers, E. C., Thomas, S. L., Smeeth, L., et al. “Incidence of Systemic Lupus Erythematosus in the United Kingdom, 1990-1999.” Arthritis and Rheumatism (Arthritis Care and Research) 57(4), (2007): 612-618.

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