Other abnormalities include:
"All the key components of the immune system are involved in the underlying mechanisms" of SLE, according to Rahman, and SLE is the prototypical autoimmune disease. The immune system must have a balance (homeostasis) between being sensitive enough to protect against infection, and being too sensitive and attacking the body's own proteins (autoimmunity). From an evolutionary perspective, according to Crow, the population must have enough genetic diversity to protect itself against a wide range of possible infection; some genetic combinations result in autoimmunity. The likely environmental triggers include ultraviolet light, drugs, and viruses. These stimuli cause the destruction of cells and expose their DNA, histones, and other proteins, particularly parts of the cell nucleus. Because of genetic variations in different components of the immune system, in some people the immune system attacks these nuclear-related proteins and produces antibodies against them. Ultimately, these antibody complexes damage blood vessels in critical areas of the body, such as the glomeruli of the kidney; these antibody attacks are the cause of SLE. Researchers are now identifying the individual genes, the proteins they produce, and their role in the immune system. Each protein is a link on the autoimmune chain, and researchers are trying to find drugs to break each of those links.
SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II involvement.Genetics: The first mechanism may arise genetically. Research indicates that SLE may have a genetic link. Lupus does run in families, but no single "lupus gene" has yet been identified. Instead, multiple genes appear to influence a person's chance of developing lupus when triggered by environmental factors. The most important genes are located on chromosome 6, where mutations may occur randomly (de novo) or may be inherited. Additionally, people with SLE have an altered RUNX-1 binding site, which may be either cause or contributor (or both) to the condition. Altered binding sites for RUNX-1 have also been found in people with psoriasis and rheumatoid arthritis.Environmental triggers: The second mechanism may be due to environmental factors. These factors may not only exacerbate existing lupus conditions but also trigger the initial onset. They include certain medications (such as some antidepressants and antibiotics), extreme stress, exposure to sunlight, hormones, and infections. Some researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease. UV radiation has been shown to trigger the photosensitive lupus rash, but some evidence also suggests that UV light is capable of altering the structure of the DNA, leading to the creation of autoantibodies. Some researchers have found that women with silicone gel-filled breast implants have produced antibodies to their own collagen, but it is not known how often these antibodies occur in the general population, and there is no data that show that these antibodies cause connective tissue diseases such as lupus.Drug reactions: Drug-induced lupus erythematosus is a reversible condition that usually occurs in patients being treated for a long-term illness. Drug-induced lupus mimics systemic lupus. However, symptoms of drug-induced lupus generally disappear once a patient is taken off the medication that triggered the episode. There are about 400 medications currently in use that can cause this condition, though the most common drugs are procainamide, hydralazine, quinidine and Phenytoin.Non-SLE forms of lupus: Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed by biopsy of skin rash on the face, neck, or scalp. Often an antinuclear antibody (ANA) test for discoid patients is negative or a low-titer positive. About 1–5% of discoid lupus patients eventually develop SLE. Clearance deficiency: The exact mechanisms for the development of systemic lupus erythematosus (SLE) are still unclear, since the pathogenesis is a multifactorial event. Beside discussed causations, impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. This includes deficient phagocytic activity and scant serum components in addition to increased apoptosis.
Monocytes isolated from whole blood of SLE patients show reduced expression of CD44 surface molecules involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBM), which are found in the germinal centres of lymph nodes, even show a definitely different morphology in patients with SLE; they are smaller or scarce and die earlier. Serum components like complement factors, CRP, and some glycoproteins are furthermore decisively important for an efficiently operating phagocytosis. In patients, these components are often missing, diminished, or inefficient.
The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondary necrosis of the cells if this ability is disturbed. Necrotic cells release nuclear fragments as potential autoantigens as well as internal danger signals, inducing maturation of dendritic cells (DC), since they have lost their membranes' integrity. Increased appearance of apoptotic cells also simulates inefficient clearance. That leads to maturation of DC and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules. Autoimmunity possibly results by the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. B and T cell tolerance for apoptotic cells is abrogated, and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in patients with cutaneous lupus erythematosus (CLE).
Accumulation in germinal centres (GC)
In healthy conditions, apoptotic lymphocytes are removed in germinal centres by specialised phagocytes, the tingible body macrophages (TBM); that’s why no free apoptotic and potential autoantigenic material can be seen. In some patients with SLE, accumulation of apoptotic debris can be observed in GC because of an ineffective clearance of apoptotic cells. In close proximity to TBM, follicular dendritic cells (FDC) are localised in GC, which attach antigen material to their surface and, in contrast to bone marrow-derived DC, neither take it up nor present it via MHC molecules. Autoreactive B cells can accidentally emerge during somatic hypermutation and migrate into the GC light zone. Autoreactive B cells, maturated coincidentally, normally don’t receive survival signals by antigen planted on follicular dendritic cells and perish by apoptosis. In the case of clearance deficiency, apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC. This serves as a germinal centre survival signal for autoreactive B-cells. After migration into the mantle zone, autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody-producing plasma cells and B memory cells. In the presence of autoreactive T cells, a chronic autoimmune disease may be the consequence.
Tingible body macrophages (TBMs) are large phagocytic cells in the germinal centers of secondary lymph nodes; they express CD68 protein. These cells normally engulf B cells that have undergone apoptosis after somatic hypermutation. In some patients with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells that may have randomly acquired self-specificity through somatic hypermutation.
Some physicians make a diagnosis on the basis of the ACR classification criteria (see below). The criteria, however, were established mainly for use in scientific research (i.e., inclusion in randomized controlled trials), and patients may have lupus but never meet the full criteria.
Antinuclear antibody testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay of serologic testing for lupus. Antiphospholipid antibodies occur more often in SLE and can predispose for thrombosis. More specific are the anti-Smith and anti-dsDNA antibodies. Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and renal function (disturbed if the kidney is involved), liver enzymes, and a complete blood count.
Previously, the lupus erythematosus (LE) cell test was not commonly used for diagnosis because those LE cells are only found in 50–75% of SLE patients, and are also found in some patients with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance.
A useful mnemonic for these 11 criteria is SOAP BRAIN MD: Serositis (8), Oral ulcers (4), Arthritis (5), Photosensitivity (3), Blood Changes (9), Renal involvement (proteinuria or casts) (6), ANA (10), Immunological changes (11), Neurological signs (seizures, frank psychosis) (7), Malar Rash (1), Discoid Rash (2).
Another popular mnemonic is DOPAMIN RASH: Discoid rash (2), Oral ulcers (4), Photosensitivity (3), Arthritis (5), Malar Rash (1), Immunological changes (11), Neurological signs (seizures, frank psychosis) (7), Renal involvement (proteinuria or casts) (6), ANA (10), Serositis (8), Hematological Changes (5).
Some patients, especially those with antiphospholipid syndrome, may have SLE without four criteria, and SLE is associated with manifestations other than those listed in the criteria.
1. Simplest classification tree: SLE is diagnosed if the patient has an immunologic disorder (anti-DNA antibody, anti-Smith antibody, false positive syphilis test, or LE cells) or malar rash.
2. Full classification tree: Uses 6 criteria.
Other alternative criteria have been suggested.
Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce the incidence of flares, the process of the disease, and lower the need for steroid use; when flares occur, they are treated with corticosteroids. DMARDs commonly in use are antimalarials and immunosuppressants (e.g., methotrexate and azathioprine). Hydroxychloroquine (trade name Plaquenil) is an FDA-approved antimalarial used for constitutional, cutaneous, and articular manifestations, while cyclophosphamide (trade names Cytoxan and Neosar) is used for severe glomerulonephritis or other organ-damaging complications. In 2005, mycophenolic acid (trade name CellCept) became accepted for treatment of lupus nephritis.
In more severe cases, medications that modulate the immune system (primarily corticosteroids and immunosuppressants) are used to control the disease and prevent recurrence of symptoms (known as flares). Depending on the dosage, patients who require steroids may develop side effects such as central obesity, puffy round face, diabetes mellitus, large appetite, difficulty sleeping and osteoporosis. Those side effects can subside if and when the large initial dosage is reduced, but long-term use of even low doses can cause elevated blood pressure and cataracts.
Since a large percentage of lupus patients suffer from varying amounts of chronic pain, stronger prescription analgesics may be used if over-the-counter drugs (mainly nonsteroidal anti-inflammatory drugs) do not provide effective relief. Moderate pain in lupus patients is typically treated with mild prescription opiates such as dextropropoxyphene (trade name Darvocet) and co-codamol (trade name Tylenol #3). Moderate to severe chronic pain is treated with stronger opioids, such as hydrocodone (trade names Lorcet, Lortab, Norco, Vicodin, Vicoprofen) or longer-acting continuous-release opioids, such as oxycodone (trade name OxyContin), MS Contin, or Methadone. The Fentanyl Duragesic Transdermal patch is also a widely used treatment option for the chronic pain of lupus complications because of its long-acting timed release and ease of use. When opioids are used for prolonged periods, drug tolerance, chemical dependency, and (rarely) addiction may occur. Opiate addiction is not typically a concern for lupus patients, since the condition is not likely to ever completely disappear. Thus, lifelong treatment with opioids is fairly common in lupus patients who exhibit chronic pain symptoms, accompanied by periodic titration that is typical of any long-term opioid regimen.
Although SLE can occur in anyone, at any age, it is most common in women of childbearing age. It affects 1 in 4000 people in the United States, again with women becoming afflicted far more often than men. The disease appears to be more prevalent in women of African, Asian, Hispanic, and Native American origin, but this may be due to socioeconomic factors. People with relatives who suffer from SLE, rheumatoid arthritis, or thrombotic thrombocytopenic purpura are at a slightly higher risk than the general population.
The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern. The classical period began when the disease was first recognized in the Middle Ages and saw the description of the dermatological manifestation of the disorder. The term lupus is attributed to 12th-century physician Rogerius, who used it to describe the classic malar rash. The neoclassical period was heralded by Móric Kaposi's recognition in 1872 of the systemic manifestations of the disease. The modern period began in 1948 with the discovery of the LE cell (the lupus erythematosus cell—a misnomer, as it occurs with other diseases as well) and is characterised by advances in our knowledge of the pathophysiology and clinical-laboratory features of the disease, as well as advances in treatment.
Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment to patients until the middle of the twentieth century, when Hench discovered the efficacy of corticosteroids in the treatment of SLE.
Intestinal pseudo-obstruction as a presenting manifestation of systemic lupus erythematosus: case report and review of the literature.(Case Report)
Feb 01, 2004; Abstract: A case of intestinal pseudo-obstruction as a presenting manifestation of systemic lupus erythematosus is presented....
Investigators at Kaohsiung Medical University, Graduate Institute of Medicine zero in on systemic lupus erythematosus.(Report)
May 13, 2010; Researchers detail in 'Suppressor of cytokine signaling 1 gene expression and polymorphisms in systemic lupus erythematosus,' new...
New systemic lupus erythematosus research from Medical University of Lodz, Department of Dermatology discussed.(Clinical report)
May 10, 2010; Scientists discuss in 'Effect of chloroquine phosphate treatment on serum MMP-9 and TIMP-1 levels in patients with systemic lupus...