SYSTEMIC LUPUS ERYTHEMATOSUS

DEFINITION AND PREVALENCE Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs and cells undergo damage mediated by tissue-binding autoantibodies and immune complexes. Ninety percent of patients are women of child-bearing years; people of both sexes, all ages, and all ethnic groups are susceptible. Prevalence of SLE in the United States is 15-50 per 100,000; the highest prevalence among ethnic groups studied is in African Americans. PATHOGENESIS AND ETIOLOGY The proposed pathogenic mechanisms of SLE are interactions between susceptibility genes and environmental factors resulting in abnormal immune responses. Those responses include (1) activation of innate immunity (dendritic cells) by CpG DNA, DNA inn immune complex, and RNA in RNA/protein self-antigens; (2) lowered activation thresholds of adoptive immunity cells (antigenspecific T and B lymphocytes); (3) ineffective regulatory and inbitory CD4+ and CD8+ T cells; and (4) reduced clearance of apoptotic cells and of immune complexes. SLE is a multiple disease. A region on chromosomes 16 contains genes that predispose to SLE, Rheumatoid arthritis, Psoriasis, and Crohns disease. All these gene combination influence immune response to the external and internal environment; when such responses are too high and/or too prolonged, autoimmune disease results. Female sex is permissive for SLE; females of many mammalian species make higher antibody responses than males. Women exposed to estrogen-containing oral contraceptives or hormone replacement have an increased risk of developing SLE. Several environment stimuli may influence SLE. Exposure to ultraviolet light cause flares of SLE in approximately 70% of patients, possibly by increasing apoptosis in skin cells or by altering DNA and intracellular proteins to make them antigenic. It is likely that some infections induce a normal immune response that matures to contain some T and B cells that recognize self-antigens. Epstein-Barr virus (EBV) may be one infectious agent that can trigger SLE in susceptible individuals. Children and adults whit SLE are more likely to be infected by EBV than age-, sex-, and ethnicity-matched controls. EBV activates and infects B lymphocytes and survives in those cells for decades; it also contains amino acid sequences that mimic sequences human spliceosomes. Thus, interplay between genetic susceptibility, environment, sex, and abnormal immune response results in autoimmunity. PATHOLOGY In SLE, biopsies of affected skin show deposition of Ig at the dermal-epidermal junction (DEJ), injury to basal keratinocytes, and inflammation dominated by T lymphocytes in DEJ and around blood vessels and dermal appendages. In renal biopsies, the pattern and severity of injury are important in diagnosis and in selecting the best therapy. ISN/RPS classification is the addition of a for active and c for chronic changes, giving the physician information regarding the potential reversibility of disease. All the classification systems focus of glomerular disease, although the presence of tabular interstitial and vascular disease is

important to clinical outcomes. In general, Class III and IV disease, as well class III or IV disease, should be treated with aggressive immunosuppression if possible, because there is a high risk for end-stage renal disease (ESRD) if patients are untreated or undertreated. Treatment for lupus nephritis is not recommended in patients with class I or II disease or with extensive irreversible changes. In children, a diagnosis of SLE can be histology without meeting additional diagnostic criteria. Histology abnormalities in blood vessels may also determine therapy. Patterns of vasculitis are not specific for SLE buy may indicate active disease: leukocytoclastic vasculitis is most common. Lymph node biopsies are usually performed to rule out infection or malignancies. In SLE, they show nonspecific diffuse chronic inflammation. DIAGNOSIS Diagnostic criteria for SLE Malar rash Discoid rash Photosensitivity Oral Ulcers Arthritis Fixed erythema, falt or raised, over the malar eminences Erythermatous circular raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur Exposure to UV light causes rash Includes oral and nasopharyngeal ulcers, observed by physician Nonerosive of 2 or more peripheral joints, with tenderness, swelling, or effusion Pleuritis or pericarditis documented by ECG or rub or evidence of effusion Protenuria >0.5 g/d or greater than equal to 3+, or cellular cats Seizure or psychosis without other causes Hemolytic anemia or leucopenia or lymphopenia or thrombocytopenia in the absence of offending drugs Anti-dsDNA, anti-Sm, and/or anti-phospholipid

Serosotis Renal disorder Neurologic disorder Hematologic disorder Immunologic disorder Anti-nuclear An abnormal titer of ANA by immunofluorescence or an equivalent assay at anitodies any point in time in the absence of drugs known to induce ANAs The criteria are intended for confirming the diagnosis of SLE the author uses them in individuals history, makes it likely that the probability that a disease is SLE. Any combination of 4 of 11 criteria, well documented at any time during an individuals history, makes it likely that patient has SLE. Antinuclear antibodies (ANA) are positive in >98% of patient during the course of disease. High-tire IgG antibodies to double-standard DNA and antibodies to the Sm antigen are both specific for SLE. OVERVIEW AND SYSTEMATIC MANIFESTATION Severity of SLE varies from mild and intermittent to serve and fulminant. Systemic symptoms, particular fatigue and myalgias/arthralgias, are present most of the time. Severe systemic illness requiring glucocorticoid therapy can occur with fever, prostration, weight loss, and anemia with or without other organ-targeted manifestations. MUSCULOSKELETAL MANIFESTATION Most people with SLE have intermittent polyarthritis, varying from mild to disabling, characterized by soft tissue swelling and tenderness in joint, most commonly in hands, wrist, and knees. Erosions on joint x-rays are rare; their presence suggests a non-lupus inflammatory arthropathy such as rheumatoid arthritis. IF pain persists in a single joint, such as knee, shoulder, or hip, a diagnosis of ischemic necrosis of bone should be considered, particularly if there are no other

manifestations of active SLE. The prevalence of ischemic necrosis of bone is increased in SLE, especially inpatients treated with systemic glucocotricoids. Myositis with clinical muscle weakness, elevated creatine kinase levels, positive MRI scan, and muscle necrosis and inflammation on biopsy can occur. Glucocorticoid therapies (commonly) and antimalarial therapies (rarely) can also cause muscle weakness; these adverse effects must be distinguished from active disease. CUTANEOUS MANIFESTATIONS Lupus dermatitis can be classified as discoid lupus erythematosus (DLE), systemic rash, subcute cutaneous lupus erythematosus (SCLE), or other Discoid lesions are roughly circular with slight raised, scaly hyperpigmented erythematous rims and depigmented, atrophic centers in which all dermal appendages are permanently destroyed. Lesions can be disfiguring, particularly on the face and scalp. Treament consist primarily of topical or locally injected glucocorticoids and systemic antimalarials. The most common SLE rash is a photosensitive, slight raised erythema, occasionally scaly, on the face (particularly the cheeks and nose the butterfly rash), ears, chin, V region of the neck, upper back, and extensor surfaces of the arms. Worsening of this rash often accompanies flare of systemic disease. SCLE consist of scaly red patches similar to pscoriasis or circular flat redrimmed lesions. Patients with these manifestations are exquisitely photosensitive; most have antibodies to Ro (SS-A). Other SLE rashes include recurring urticaria, lichen planus-like dermatitis, bullae, and panniculitis (lupus profundus). Rashes can be minor or severe; they may be the major disease manifestation. Small, painful ulcerarions on the oral or nasal mucosa are common in SLE; the lesions resemble aphthous ulcers. RENAL MANIFESTATIONS Nehritis is usually the most serious manifestations of SLE, since nephritis and infections are the leading cause of mortality in the 1st decade of disease. Nephritis is asymptomatic in most lupus patients.. the classification of lupus nephritis is primarily histologic. Renal biopsy usually have microscopic hematuria and proteinuria; approximately develop nephritic syndrome and develop hypertension. If deiffuse proliferative glomerulonephritis (DPGN) is untreated, virtually patients develop ESRD within 2 years of diagnosis. A small proportion of SLE patients with proteinuria have membranous glomelular changes without proliferation on reanl biopsy. NERVOUS SYSTEM MANIFESTATIONS CNS and PNS manifestations of SLE; in some patients are the major cause of morbidity and mortality. Symptoms related to SLE are caused by diffuse process or vascular occlusive disease. The most common manifestation of diffuse CNS lupus is cognitive dysfunction, including difficulties with memory and reasoning. Headaches often indicate SLE flare; when milder they are difficult to distinguish from migraine or tension headaches. Seizure ma be caused by lupus; treatment requires both antiseizure and immunosuppressive therapies. Psychosis can be a dominant manifestation of SLE usually occurs in the 1st weeks of glucocorticoid therapy. Myelopathy is not rare and is often disabling. VASCULAR OCCLUSIONS The prevalence of TIAs, strokes, and MIs is increased in patients with SLE. Antiphospolipid antibodies are associated with hypercoagubility and acute thrombotic events, whereas chronic disease is associated with accelerated atherosclerosis. In SLE, MIs are primarily manifestations of accelerated atherosclerosis. Increased risk for vascular events is 7-10 fold overall, and higher in women <45 years old with SLE. Long-term coagulation is the therapy of choice. PULMONARY MANIFESTATIONS Most common pulmonary manifestation of SLE is pleuritis with or without pleural effusion. When mild, responds to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). More severe requires a brief course of glucocorticoid therapy. Pulmonary infiltrates also occur as manifestation of SLE. Life threatening manifestations include interstitial inflammation leading to fibrosis,

shringking lung syndrome, intraalveolar hemorrhage, may require early aggressive immunosupressive therapy as well as supportive care. CARDIAC MANIFESTATIONS Pericarditis is the most frequent cardiac manifestation, usually responds to ani-inflammatory therapy and infrequently leads to tamponade. More serious cardiac manifestations are myocarditis and fibrinous endocarditis of Libman-Sacks. Endocardial involvement can lead to valvular insufficiencies, most commonly of the mitral or aortic valve, or to embolic events. HEMATOLOGIC MANIFESTATIONS The most frequent hematologic manifestation of SLE is anemia, usually normochromic, reflecting chronic illness. Hemolysis can be rapid in onset and severe which require high-dose of glucocorticoid therapy in which effective in most patients. Leukopenia is also common and almost always consists of lymphopenia. Thrombocytopenia is also a problem in which high-dose of glucocorticoid therapy is usually effective in 1st few episode. GAsTROINTESTINAL MANIFESTATIONS Nausea, sometimes with vomiting and diarrhea can be a manifestation of an SLE flare. These manifestations usually improve promptly with glucoccorticoid therapy. Complications such as vasculitis; perforations, ischemia, bleding, and sepsis, immunosuppressive therapy with gucocorticoids is recommended for short-term control. OCULAR MANIFESTATIONS Sicca syndrome (Sjgrens syndrome) and non specific conjunctivitis are common in SLE and rarely threaten vision. Retinal vasculitis and optic neuritis are the serious manifestations. Blindness can develop. Aggressive immunosuppressive is recommended. The use of glucocorticoid therapy can complicate cataracts and glaucoma. LABORATORY TESTS CBC, platelet count and urinalysis are used for screening test to detect abnormalities that contribute to the diagnosis. During the course of SLE, tests for hemoglobin levels and serum levels of creatinine or albumin are done. MANAGEMENT NSAIDs Topical glucocorticoids Topical Sunscreens Hydroxychloroquine DHEA (dehydroepiandrosterone) Methotrexate Glucocorticoids Methyprednisolone sodium succinate Cyclophosphamideb IV Mycophenolate mofetilb Azathioprineb

PROGNOSIS and SURVIVAL Survival with SLE in US, Canada, Europe and China is approximately 95% at 5 years, 90% at 10 years and 78% at 20 years. In US, African-Americans and Hispanic Americans with mestizo heritage have a worse prognosis than Caucasians. Glucocorticoid therapies is the sole therapy for

severe lupus. Poor prognosis are those with high serum creatinenine levels, hypertension, nephritic syndrome, anemia, hypoalbumenia, hypoconplementemia, aPL, male sex, and ethnicity. Disabilities in SLE is common due to chronic fatigue, arthritis, and pain. Leading cause of death are systemic disease activity, renal failure, and infections. Thrombotic events become increasingly frequent causes of mortality.