Overview of the therapy and prognosis of systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a chronic, occasionally life threatening, multisystem disorder. Patients suffer from a wide array of symptoms and have a variable prognosis depending upon the severity and type of organ involvement. Due to its uncertain course, effective treatment requires ongoing patient-doctor communication to correctly interpret laboratory tests, alleviate symptoms, prevent and treat relapses, and lessen side effects related to drug therapy.
The treatment of specific organ involvement is discussed separately.
DETERMINATION OF ACTIVITY AND SEVERITY – An effective therapeutic regimen first requires the accurate determination of both disease activity and severity. Disease activity usually refers to the degree of inflammation, while severity implies that organ function and perhaps its underlying structure is quantitatively impaired. The degree of organ dysfunction has been referred to as the "damage index".
The presence of severe organ dysfunction does not necessarily imply ongoing inflammation. As an example, marked proteinuria and decreased glomerular filtration rate may result from either active inflammation or inactive scarring. The ability to differentiate between these two possibilities is extremely important, since immunosuppressive therapy is not indicated in the latter setting.
Markers of activity – Disease activity is assessed using a combination of the clinical history, physical examination, organ specific functional tests, and serologic studies. As an example, active SLE (particularly lupus nephritis) is commonly associated with a rise in IgG anti-double-stranded DNA titers , a fall in complement levels (especially CH50, C3 and C4), and an elevation in complement split products . Increases in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are also commonly seen with active disease. CRP is particularly elevated in patients with infection .
However, not all patients with these serologic markers have active disease and these markers do not necessarily predict disease exacerbation . In one study, for example, 12 percent of patients with hypocomplementemia and elevated anti-DNA antibody titers had no clinical evidence of active disease . We favor an approach in which such patients are closely monitored; therapy is adjusted if there are signs of clinical worsening of the disease. However, some advocate the use of higher doses of prednisone (30 mg/day) in this setting, which they claim results in fewer flares and a lower overall cumulative dose of prednisone.
Other, more investigational laboratory tests also may reflect disease activity including:
• Soluble T-cell activation markers – Elevated serum levels of CD25, CD27, CD30, and CD50 (ICAM-3).
• Cytokines – Elevated serum levels of interleukin (IL)-2 receptor , IL-6, gamma interferon, and IL-10 . A variety of other changes in cytokines have also been described.
• Adhesion molecules – Elevated serum levels of vascular cell adhesion molecule (VCAM)-1, P-selectin , and endothelium leukocyte adhesion molecule (ELAM)-1 ; different studies have found either elevated or normal levels of intercellular adhesion molecule (ICAM)-1, while E-selectin levels are generally unchanged.
• Cell surface expression – Cell surface expression of VLA-4 and LFA-1 in lupus vasculitis ; LFA-1, E-selectin, VCAM-1, and ICAM-1 in SLE.
• Other – A number of other changes have been reported including elevated serum prolactin levels in some patients with SLE, which correlate somewhat with clinical activity , the presence of soluble HLA Class I antigen and antiendothelial cell antibodies ,and increased expression of complement receptor 2 (CR2) on B lymphocytes , and of molecular markers of hemostasis, such as thrombin-antithrombin III complexes and D-dimer fragments .
A number of research/academic protocols (SLEDAI, SLAM, BILAG, etc) have been designed in an attempt to accurately monitor disease activity . They all use a combination of history, examination and laboratory data; these protocols may have general applicability once they are simplified.
GENERAL TREATMENT CONSIDERATIONS – Although organ involvement requires specific drug therapy, a number of general issues are applicable to every patient with SLE.
Diet and nutrition – Limited data exists concerning the effect of dietary modification in SLE. One study reported that frequent intake of meat was associated with more active and progressive disease . In contrast, dietary fish oil has been reported to be beneficial. One double-blind, randomized study found that 14 of 17 patients who ingested 20 g/day of eicosapentaenoic acid achieved either a useful or ideal status; in contrast, 13 of 17 receiving placebo were worse or had not changed . These findings await confirmation; at present, we do not recommend fish oil supplements in the treatment of SLE.
A conservative approach is to recommend a balanced diet consisting of carbohydrates, proteins, and fats. However, the diet should be modified based upon disease activity and the response to therapy:
• Patients with active inflammatory disease and fever may require an increase in caloric intake.
• Corticosteroids enhance appetite, resulting in potentially significant weight gain. Hunger can be somewhat lessened by the ingestion of water, antacids, and/or H2 blockers. If, however, weight gain is significant, patients should receive instruction on low calorie diets.
• Significant hyperlipidemia may be induced by the nephrotic syndrome or the administration of corticosteroids . One study, for example, found that increasing the dose of prednisone by 10 mg per day was associated with an elevation in serum cholesterol of 7.5 mg/dL (0.2 mmol/L) .
Patients with hyperlipidemia should be encouraged to eat a low fat diet . A lipid-lowering agent (usually a statin) should be considered if cholesterol levels remain high despite a change in diet.
• Vitamins are rarely needed when patients eat a balanced diet. However, a daily multivitamin should be taken by patients who are not able to obtain an adequate diet or who are dieting to lose weight.
• Patients on long-term steroids and postmenopausal women should also ingest 400 to 800 units of Vitamin D plus 1000 mg of calcium per day to minimize the degree of bone loss.
• Herbs are of unproven benefit, and may cause harm.
Exercise – Inactivity produced by acute illness causes a rapid loss of muscle mass and stamina. Fatigue may therefore ensue once the illness subsides. This can usually treated with graded exercise. In selected refractory cases, relief of fatigue can be obtained with prednisone , antimalarials, or dehydroepiandrosterone (DHEA) .
Immunizations – It had been previously thought that immunization could exacerbate SLE. However, influenza vaccine has now been shown to be safe and effective ; pneumococcal vaccine is also safe but resultant antibody titers are somewhat less in patients with SLE than in controls . In contrast, it is inadvisable to immunize potentially immunosuppressed patients with live vaccines.
Avoidance of specific medications – Anecdotal data suggests that sulfonamides and penicillin (but not the synthetic penicillins) may cause exacerbations and should therefore be avoided . In contrast, medications that cause drug-induced lupus, however, such as procainamide and hydralazine, do not cause exacerbations of idiopathic SLE. This observation is a presumed reflection of the pathogenetic differences between the two disorders.
Pregnancy and contraception – Pregnancy should be avoided during active disease (especially with significant organ impairment) due to the high risk of miscarriage. Women with SLE should be counseled not to become pregnant until the disease has been quiescent for at least six months.
Oral contraceptives containing high dose estrogens can cause exacerbations of SLE. However, this complication rarely occurs with the current use of low dose estrogen or progesterone containing compounds. Patients with migraine headaches, Raynaud's syndrome, a history of phlebitis, or antiphospholipid antibodies probably should not be treated with oral contraceptives. We also recommend avoidance of intrauterine devices due to the increased risk of infection.
Pregnant patients with active lupus are generally managed with corticosteroids. Other drugs used during pregnancy include NSAIDs and hydroxychloroquine (probably safe). Cyclophosphamide and methotrexate are contraindicated; however, azathioprine can be cautiously used.
TREATMENT OF SPECIFIC ORGAN INVOLVEMENT – A number of medications are commonly used in the treatment of SLE, including nonsteroidal antiinflammatory drugs (NSAIDs), antimalarials (primarily hydroxychloroquine), corticosteroids, and immunosuppressive agents (primarily cyclophosphamide and azathioprine). What follows is a general overview of which drugs are preferred in selected clinical settings.
• NSAIDs are generally effective for musculoskeletal complaints and mild serositis.
• Antimalarials are most useful for skin manifestations and for musculoskeletal complaints which do not adequately respond to NSAIDs.
• Systemic corticosteroids used alone or in combination with immunosuppressive agents are reserved for patients with significant organ involvement, particularly renal and central nervous system disease.
• Treatment with prednisone as soon as a significant rise in anti-dsDNA occurred prevented relapses in most cases in a study of 156 patients . As noted above, however, we follow such patients closely but do not treat titers in the absence of clinical evidence of active disease
A number of other therapeutic approaches have been tried or are under investigation in SLE. These include intravenous immune globulin , DHEA , thalidomide, bromocriptine , and zileuton , and cyclosporine .
PROGNOSIS – SLE can run a varied clinical course, ranging from a relatively benign illness to a rapidly progressive disease with fulminant organ failure and death. Most patients have a relapsing and remitting course, which may be associated with the use of high dose steroids during the treatment of severe flares.
Patient survival – The survival rate in SLE has dramatically increased over the last several decades from approximately 40 percent at five years in the 1950s to approximately 90 percent at 10 years at the present time . The likelihood of survival can be ranked on the basis of organ involvement (skin and musculoskeletal best, central nervous system and renal worst) and on the number of American College of Rheumatology criteria for SLE (the higher the number the worse the prognosis) .
The improvement in patient survival is probably due to multiple factors. These include increased disease recognition with more sensitive diagnostic tests , earlier diagnosis or treatment, the inclusion of milder cases, and increasingly judicious therapy and prompt treatment of complications .
The major cause of death in the first few years of illness is active disease (eg, CNS, renal, or cardiovascular disease), while late deaths are either caused by the illness or treatment complications (including infection and coronary disease).
• Serious infection is most often due to immunosuppressive therapy. Patients at particular risk are those treated with both corticosteroids and cyclophosphamide, especially if the white blood cell count is less than 3000/µL and/or high-dose steroids are given . In one report of 100 patients with SLE who were treated with cyclophosphamide, for example, infection occurred in 45 percent; this was significantly higher than the 12 percent incidence noted in 43 other patients treated only with high dose steroids .
• Premature coronary artery disease is being increasingly recognized as a cause of late mortality; this has been primarily attributed to accelerated atherosclerosis associated with corticosteroid use .
One study, for example, evaluated the causes of death in 144 of 408 patients with SLE followed over a mean period of 11 years . Mortality was most commonly due to active lupus (34 percent), infection (22 percent), cardiovascular disease (16 percent), and cancer (six percent). Deaths which resulted directly from SLE and infection were common among younger patients; the risk of death directly due to SLE was highest in the first three years after diagnosis.
The relation of SLE to cancer is unclear because conflicting data have been reported. Three studies have found no change in the cancer rate , a decrease in cancer but an increase in non-Hodgkin's lymphoma , and an elevation in the overall cancer rate . The largest study of 1585 Danish patients with SLE found a five-fold increase in the risk of non-Hodgkins lymphoma, as well as an increase in lung, liver, and vagina/vulva cancer.
Poor prognostic for survival in SLE include:
• Renal disease (especially diffuse proliferative glomerulonephritis)
• Hypertension
• Male sex
• Young age
• Older age at presentation
• Black race, which may primarily reflect low socioeconomic status
• Poor socioeconomic status
• Presence of antiphospholipid antibodies
• High overall disease activity
Morbidity – Despite the reduction in long-term mortality, patients with SLE are still at risk for significant morbidity due both to active disease and the side effects of drugs such as corticosteroids and cytotoxic agents. Steroid-induced avascular necrosis of the hips and knees has become a particularly important problem as patients live longer with their illness.
Remission – Although a major focus has been on improving mortality and morbidity in SLE, it is becoming increasingly recognized that many patients go into a clinical remission requiring no treatment. In a recent study of 667 patients, approximately 25 percent had treatment-free remission lasting for at least a year. Remission occurred in 50 percent of those with disease over 18 years duration, and in 75 percent of those with disease over 30 years duration. Remission was also seen in some patients who had had severe renal disease. In another report, six percent of 300 patients went into long-lasting clinical and serologic remission (ie, a negative ANA).
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