Systemic lupus erythematosus is a multi-organ, autoimmune inflammatory disease. The annual incidence of SLE in the United States ranges from 2.0 to 7.6 cases per 100,000 persons per year. This review examines the clinical course of SLE, various treatment options, and the treatment of specific manifestations of the disease such as lupus nephritis.
Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects multiple organ systems including the skin, kidneys, and brain. The exact cause is unknown but genetic factors, ethnic origin, environmental factors, and medications may all be involved in its development. Women, African-Americans, and Hispanics are more likely to develop SLE. Earlier diagnosis and more effective treatment options have significantly improved 5-, 10-, and 20-year survival rates. Nonpharmacologic treatment is limited and mainly involves proper sun protection-avoidance, protective clothing, and sunscreen. Pharmacologic treatment is usually tailored to the specific symptoms or organ systems that are involved. Treatment modalities include steroids, antimalarials, and cytotoxic/immunosuppressive agents. This review will examine the clinical course of SLE, various treatment options, and the treatment of specific manifestations of the disease such as lupus nephritis. (Formulary. 2011;46:178–194.)
The development of SLE is a complex immune process that is brought about by dysregulation of B- and T-lymphocytes, the production of auto-antibodies, and the formation of immune complexes.11 Cytokines are thought to play a key role in SLE; however, the extent to which they affect progression of lupus is not clear. Their involvement may help explain the variations seen in the clinical manifestations of patients. More research is needed to identify the role of cytokines in order to better understand the disease progression as well as find new treatment options.
While it is known that the immune system plays a role in the development of the disease, what causes the immune system to function abnormally is unknown. It is speculated that environmental factors play a role, but the data have not consistently supported this theory.12,13 There is, however, evidence to suggest that genetic components play a role. Several immunologic gene abnormalities (eg, interferon regulatory factor 5, protein tyrosine phosphatase nonreceptor type 22, and integrin alpha M) have been identified. Additionally, research in homozygous twins has shown a higher incidence of SLE in families where the prevalence of the disease in other family members was low.2,14 Furthermore, those with infantile-onset SLE occurring within the first year of life have a high incidence of having family members with a history of autoimmune diseases.15
There is also some evidence that hormone abnormalities are associated with SLE. Estrogen and androgen metabolism have been found to differ in men and women with SLE compared with healthy controls.16 For example, women with SLE metabolize estrogen to a more potent form, 16a-hydroxyestrone, instead of 2-hydroxyestrone, and can have irregular menstruation cycles and increased risk of miscarriage. Prolactin levels can also be elevated in patients with SLE.16 Use of hormone replacement therapy has also been shown to increase the risk of developing SLE.17 Infection with the Epstein-Barr virus has been associated with the production of autoantibodies that are present in up to 38% of patients with SLE.18 However, it is not clear if these actually lead to the development of SLE or just occur concomitantly.
Several mechanisms have been implicated in DILE, including genetics and auto-antibody production. Agents such as procainamide, hydralazine, and isoniazid generally cause DILE in patients with genetic abnormalities. These medications all undergo acetylation as part of their metabolism, so patients who are slow acetylators tend to have more problems with DILE compared with those who have normal or fast acetylation. Another potential cause of DILE involves hapten-like reactions where the drug or its metabolites bind to proteins rendering them foreign to the body. This in turn leads to an autoimmune response by the body. Other drugs, like the anti-TNF agents, are thought to produce auto-antibodies by causing direct damage to the immune system.8–10
DIAGNOSIS AND CLINICAL PRESENTATION
Diagnosis is based on classification criteria established by the American College of Rheumatology (ACR). A minimum of 4 of the 11 ACR criteria should be met in order to qualify as SLE for clinical trials. The 11 ACR criteria are broken into systems: cutaneous, musculosketetal nonerosive arthritis, cardiopulmonary pleuritis or pericarditis, renal, neurological disorder with seizures or psychosis due to unknown causes, and laboratory.20 A rheumatologist or nephrologist may diagnose a patient if the patient meets only 3 of the criteria (1 must be clinical and 1 must be serologic) and has other clinical manifestations such as alopecia, skin vasculitis, Raynaud's phenomenon, or lung fibrosis.5 Some patients may have only 1 organ system involved or only have some of the manifestations of SLE and will, therefore, not be diagnosed with SLE under the ACR criteria. These patients are classified as having "incomplete" or "latent" lupus.16 Furthermore, patients might have SLE for years before enough criteria are met to classify them as having SLE, with a mean of 2 years between first manifestations and final diagnosis.2
Clinical presentation can include nonspecific symptoms (eg, severe fatigue, fever, weight loss, and lymphadenopathy). Common skin manifestations include a malar or butterfly rash, with sun-induced macules or papules occurring on the face, or a generalized rash occurring on the body, which may or may not be sun induced. Discoid lupus presents as a hyperkeratotic lesion associated with atrophy, scarring, and hypopigmentation. Ninety percent of patients have joint inflammation such as arthralgia, arthritis, tendinitis, or early morning stiffness generally in the knees, wrists, and hands. Joint inflammation tends not to cause permanent damage. Men with SLE tend to have less arthritis, but serositis can be more predominant than in women.5
Another common feature, occurring in 50% of cases, is mucosal ulceration, usually oral. Since methotrexate can also cause these ulcerations, it can be difficult to determine if the ulceration is induced by SLE or the drugs used to treat it. Diffuse alopecia can generally occur when the disease is active and is usually reversible during remission. Patchy alopecia, on the other hand, may lead to scarring and can become permanent.5 Cardiovascular and respiratory symptoms are also common and include chest pain on inspiration due to pleurisy or pericarditis. Cardiovascular disease (eg, myocardial infarction) is secondary to accelerated atherosclerosis and other risks (hypertension, hypercholesterolemia, hypertriglyceridemia, diabetes, and heart failure), which can also exacerbate cardiovascular disease in SLE. The risk of hospitalization for an acute myocardial infarction was 2.27 times greater for lupus patients aged 18 to 44 years than for non-lupus patients.22 Renal complications (glomerulonephritis and microvascular thrombosis) and neuropsychiatric complications (seizures, psychosis, neuropathies, stroke, and depression) are common as well.23 Ophthalmic and gastrointestinal manifestations are usually uncommon but can be serious, including keratoconjunctivitis sicca, pancreatitis, hepatitis, and subacute bowel obstruction.
Age at onset affects clinical presentation. Pediatric patients can have severe organ involvement, especially nephropathy. Neurologic and hematologic manifestations such as thrombocytopenia and hemolytic anemia are common early features in pediatric SLE, whereas skin and joint manifestations are less common.2 Arthritis, fever, serositis, sicca symptoms, Raynaud's syndrome, lung disease, and neuropsychiatric symptoms are more common in the elderly population with SLE, while malar rash, discoid lupus, and glomerulonephritis are less common.4
DILE can present with different clinical features. Symptoms in DILE are generally milder, with arthralgia often being the only symptom that these patients have. Arthralgia and myalgia are both common, occurring in 90% and 50% of patients, respectively. Other common symptoms include fever, pleurisy, and pericarditis. Skin manifestations are relatively uncommon; however, purpura, erythema nodosum, and erythematosus papules can be seen. Additionally, renal and central nervous system (CNS) damage do not occur in the vast majority of cases. Onset of most symptoms generally occurs 4 to 20 weeks after initiation of therapy, but some cases of DILE have occurred after years of therapy.8-10
MEASURING TREATMENT OUTCOMES
Disease activity. SLE activity has 3 patterns: flare, chronic, and long quiescence. A flare or relapsing remission is an exacerbation that occurs suddenly and unpredictably; patients are usually in good health between flares. Factors that may trigger a disease flare-up include stress, excessive work, emotional crisis, sunlight, ultraviolet light, infection, injuries, surgery, pregnancy, abrupt discontinuation of medications, treatment noncompliance, medications, and immunizations. Serologic tests are not helpful in predicting flares because serologic activity of SLE may occur without clinical manifestations. Chronic SLE has persistent activity of some type such as chronic synovitis, chronic cytopenias, or active discoid lupus. This chronic activity may or may not require treatment. Patients with long quiescence have a long remission period before having additional flare-up.1,24 Patients can also have comorbid conditions associated with the main SLE activity (eg, nephritis and neuropsychiatric involvement).
Outcome measures. Disease activity may be measured with validated instruments such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA)-SLEDAI, the British Isles Lupus Assessment Group scale (BILAG), the European Concensus Lupus Activity Measure (ECLAM), or the Systemic Lupus Activity Measure (SLAM), which are good predictors of damage, reversible inflammation, and mortality. The European League Against Rheumatism (EULAR) Task Force on SLE recommends that at least 1 of these indices be used to monitor disease activity.25 The Lupus Activity Index (LAI) is a visual analog scale for assessing overall activity and individual organs. The Systemic Lupus International Cooperating Clinics/ACR (SLICC/ACR) Damage Index documents the number of items of irreversible organ damage that have occurred.26 To measure health status, the health-related quality of life (HRQOL) or 36-item short form health survey (SF-36) can be used.
Follow-up. Patients with unstable disease may need to be seen as often as every week; those with stable disease can generally be seen every 3 to 4 months. Physical examination includes skin, mucous membranes, lymph nodes, chest, heart, abdomen, extremities, and the musculoskeletal and neurologic systems. Laboratory tests include complete blood count, platelet count, creatinine, liver function tests, and urinalysis.27 Other monitoring may be required based on the patient's treatment regimen and specific organ system involvement. Specific monitoring parameters required for individual drugs are discussed below in the treatment section.
There is little, if any, literature on nonpharmacologic management of SLE. Despite the lack of evidence, EULAR and ACR guidelines do make some recommendations.24,25 All patients with SLE should practice proper sun protection as approximately one-third of patients are photosensitive. Patients should be instructed to avoid direct exposure to sunlight and use protective clothing and sunscreens that block both ultraviolet A (UVA) and UVB rays. Patients should also be counseled to avoid tanning beds. This is especially important for patients with cutaneous involvement. Smoking cessation is also recommended for all patients with SLE because current smokers have been shown to have significantly higher SLEDAI scores than previous smokers or never smokers.28
It is also important that patients maintain proper nutrition, including adequate intake of calcium and vitamin D.25 These are especially important in patients receiving long-term glucocorticoid therapy. Vitamin D levels should be monitored periodically as well, since patients are encouraged to avoid sun exposure, which could cause problems with inadequate conversion of vitamin D in the skin. In addition, it is recommended that patients exercise routinely. Patients may also need other individualized nonpharmacologic therapy based on the different comorbid conditions that may be present (such as diet and exercise recommendations for patients with cardiovascular disease).
Guidelines were developed by the ACR in 1999 and the EULAR taskforce in 2008. These are the most commonly used guidelines but do have some limitations, particularly the ACR guidelines, because of the outdated nature of the material. Newer medications are not included in the guidelines because they were not available.
SLE treatment is highly individualized and depends on symptom manifestations, organ involvement, and disease severity.24,25 Duration of therapy is also highly individualized and is based on the patient's response. Antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs) are useful in the treatment of mild symptoms such as arthralgias and cutaneous manifestations. Oral corticosteroids and cytotoxic agents are used in more severe disease. Other medications (cyclophosphamide, immunosuppressive agents, tacrolimus) may be used depending on the severity and various organ systems involved. Belimumab is a newer agent that is approved for patients with mild to moderate disease currently taking standard therapy.29
NSAIDs. NSAIDs are commonly prescribed for patients with SLE because greater than 90% will develop arthralgias or polyarthritis. Because there are limited data to support improved outcomes in SLE, NSAIDs should be used cautiously, and there are significant risks associated with long-term use.25 NSAIDs work by inhibiting cyclooxygenase-2 (COX-2), which inhibits the production of prostaglandins that mediate inflammation and pain. In addition to COX-2 inhibition, NSAIDs can also inhibit COX-1, which in turn inhibits the production of prostaglandins that protect the lining of the gastrointestinal tract. Therefore, gastrointestinal bleeding is a concern, especially in patients who are taking these medications long term and/or receiving corticosteroids. It is therefore recommended to use an NSAID with higher COX-2 selectivity, such as celecoxib, and to avoid agents with less selectivity such as piroxicam and ketorolac. Additionally, patients on long-term NSAIDs may require a proton-pump inhibitor or histamine-2 receptor blocker to help prevent complications and alleviate side effects.30 Patients requiring long-term therapy should have a complete blood count and serum creatinine level measured annually and be instructed on how to monitor for signs/symptoms of bleeding (unusual bleeding, bloody stools, and blood in the urine).24
Antimalarials. Antimalarials are used to treat and prevent flares and are particularly useful for arthralgias that are not adequately controlled with NSAIDs.24 They may also be useful in patients with cutaneous manifestations. Hydroxychloroquine is the most commonly prescribed antimalarial agent, accounting for up to 95% of the prescriptions in the United States. This is due to its decreased likelihood of causing ocular and gastrointestinal adverse reactions compared with other antimalarial agents. Hydroxychloroquine has also been shown to help maintain remission, possibly protect against vascular and thrombotic events, and to improve lipid levels.31,32 Chloroquine is another antimalarial agent that can be used.33
The mechanism of action of antimalarial agents in the treatment of SLE is not fully understood but is believed to be due to their known immunosuppressive and anti-inflammatory properties. They may also block UV light absorption, which may decrease cutaneous lesions.33
The most common side effects are gastrointestinal upset, dermatologic reactions, headache, and lightheadedness. Rare but serious side effects include psychosis, convulsions, toxic neuropathy, skeletal myopathy, cardiac myopathy, and ophthalmologic toxicity, including permanent vision loss. The ACR recommends that all patients undergo a baseline eye examination before beginning treatment with an antimalarial agent, followed by ophthalmologic assessments every 6 to 12 months.24 The American Academy of Opththalmology in 2002 published recommendations for retinopathy screening. They base their recommendations on the economical burden of frequent screening, risk level of the patient, and duration of antimalarial treatment. Since there are no standardized screening parameters, they recommend following the recommendations from the American Academy of Ophthalmology Preferred Practice Pattern based on the patient's age if they do not have risk factors.34
Glucocorticoids. Systemic glucocorticoids used alone or in combination with other immunosuppressive agents are typically reserved for patients with significant organ involvement, particularly renal or CNS.35 High doses (40 to 60 mg/d of prednisone or prednisone equivalent) are used in patients with severe SLE, while doses of 10 mg/d or less are used for milder SLE for treatment of cutaneous and musculoskeletal symptoms not responding to other therapies.24 Doses and dosage forms may vary based on severity and complications but the shortest duration possible should be used to avoid long-term complications with these medications, which may include myopathy, osteoporosis, hypertension, diabetes, atherosclerotic vascular disease, and infections. Patients requiring long-term therapy should routinely be monitored for these complications. Total cholesterol and bone density should be checked annually, and blood glucose levels should be checked every 3 to 6 months.24
Cytotoxic/immunosuppressive agents. Patients who are not responsive to antimalarials or glucocorticoids should be considered for treatment with immunosuppressive agents for more severe manifestations of the disease. Agents in this category include cyclophosphamide, azathioprine, mycophenolate mofetil, and methotrexate. The majority of data with these agents are in the area of SLE nephritis. It is important to note that mycophenolate mofetil, cyclophosphamide, azathioprine, and methotrexate must be avoided during pregnancy. Some of these agents have also shown promise in neuropsychiatric symptoms as well as in severe cutaneous manifestations of lupus.23,25,36,37
The intravenous route for administration of cyclophosphamide is generally preferred due to fewer side effects compared with oral administration. Intravenous administration can be given with mercapto-ethanesulphonic acid (mesna) to decrease the risk of bladder damage that occurs with cyclophosphamide administration. Mycophenolate has shown promise as compared with cyclophosphamide; however, long-term data are lacking, so cyclophosphamide is preferred in combination with steroids for proliferative nephritis.38
Several other agents have been tried for patients with more severe and resistant disease, including fludarabine and cladribine. Much of the evidence for these agents is from anecdotal, uncontrolled trials or very small controlled trials. Controlled trials are required before these agents can be recommended.23,36,37,39–41
Belimumab. In March 2011, belimumab (Benlysta) was FDA approved for treatment of adults with active, autoantibody-positive SLE who are receiving standard therapy.29 Belimumab has a unique mechanism of action targeting B-cell dysfunction by inhibiting B-lymphocyte stimulator (BLyS). It has been shown that decreases in BLyS levels are associated with improvement in SLE activity and increases in BLyS levels are associated with worsening SLE activity and mild/moderate flares.42
Belimumab's safety and efficacy have been evaluated in 3 randomized, double-blind, placebo-controlled studies. In all 3 studies, patients met ACR criteria for SLE and were on standard SLE therapies including corticosteroids, antimalarials, NSAIDs, and immunosuppressants (alone or in combination). Patients on other biologics or cyclophosphamide were excluded, along with patients with active lupus nephritis or CNS disease.43–46
The phase 2 study included patients who had a history of measurable autoantibodies and had coprimary outcomes of percent change in the SELENA-SLEDAI score and time to first mild/moderate or severe flare. In the study population as a whole, belimumab was well tolerated but did not significantly reduce SLE disease activity or flares. When the subgroup of seropositive patients (71.5% of population) was evaluated, they had a significantly improved response.43 This led to the evaluation and development of a novel composite end point called the SLE Responder Index (SRI) to be used as the primary end point in both phase 3 studies. The SRI uses the SELENA-SLEDAI score to determine global improvement, BILAG scores to assure no worsening in a particular organ system, and physician's global assessment scores.44
The phase 3 trials (BLISS-5245 and BLISS-7646) included only patients who were seropositive at screening, and both trials used SRI response rate at week 52 as their primary end point. BLISS-52 (n=865) and BLISS-76 (n=819) randomized patients to standard of care plus placebo, belimumab 1 mg/kg, or belimumab 10 mg/kg for 52 weeks or 76 weeks, respectively. Both studies showed significant improvement in patient response according to the SRI using the belimumab 10 mg/kg dose compared with placebo at week 52: there was a 57.6% versus 43.6% response rate, respectively (P=.0006), in BLISS-52 and 43.2% versus 33.5% response rate, respectively (P=.017), in BLISS-76. The numbers needed to treat for the BLISS-52 and BLISS-76 were 8 and 11, respectively. The 76-week results from BLISS-76 failed to show a statistically significant difference between belimumab 10 mg/kg compared with placebo in the percentage of patients responding according to the SRI (38.5% vs 32.4%, respectively; P=.13).46 Safety data through week 76 showed that belimumab was generally well tolerated, with rates of adverse events, infections, and discontinuation that were similar to placebo.46
TREATMENTS FOR SPECIFIC DISEASE MANIFESTATIONS OR PRESENTATIONS
Treatment of lupus nephritis consists of 2 phases: induction and maintenance. There is some controversy as to what agent should be used due to issues with the individual agents and limited data, particularly with maintenance therapy. Selection of the appropriate agent depends on the severity of disease, risk of adverse reactions with the different medications, desire to preserve fertility, and cost. Typically, patients will be started on a regimen of IV cyclophosphamide plus corticosteroids or mycophenolate mofetil. Meta-analyses of lupus nephritis therapies have generally shown that there is similar efficacy between mycophenolate mofetil and cyclophosphamide for induction therapy. Studies included in these analyses generally lasted between 6 and 12 months.
Cyclophosphamide in addition to corticosteroids has been shown to improve renal function by decreasing the risk of doubling serum creatinine levels (RR, 0.59; 95% CI, 0.4–0.88) and of relapsing (RR, 0.3; 95% CI, 0.1–0.94) when compared to steroids alone.50 They have, however, failed to show an improvement in mortality. Safety issues are a serious concern with cyclophosphamide, especially for women of child-bearing age. The risk of ovarian failure was significantly increased when cyclophosphamide was added to steroids compared with steroids alone (RR, 2.18; 95% CI, 1.1–4.34).25,40,51–55 Patients with proliferative renal disease should also receive standard therapy for chronic kidney disease including angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists and lipid-lowering therapies.25,40
Mycophenolate mofetil has been shown to improve outcomes in patients with more mild disease.40 The risk of relapse at 3 years, however, was increased with mycophenolate mofetil plus steroids compared to cyclophosphamide plus steroids (RR, 2.98; 95% CI, 1.1–8.11).25,38,47,51–55 According to the EULAR guidelines, more intensive therapy may be needed if patients do not have significant improvement (improvement in serum creatinine and reduction of proteinuria to <1 g/d) after 6 months of treatment.25
Azathioprine is another possible treatment option for induction therapy. When added to steroids, it decreased all-cause mortality (RR, 0.6; 95% CI, 0.36–0.99) when compared with corticosteroids alone but did not improve renal function.47 Azathioprine did not increase the risk of ovarian failure. Triple combination therapy with cyclophosphamide, azathioprine, and steroids is not recommended since the only benefit seen was an improvement in the risk of having the serum creatinine double.38,47
Studies examining long-term maintenance therapy are limited. The MAINTAIN trial was designed to compare the long-term effects of mycophenolate mofetil and azathioprine. Patients had WHO class III–V renal disease and met ACR criteria for SLE. Patients were randomized to the azathioprine (azathioprine + glucocorticoids + cyclophosphamide) or mycophenolate mofetil groups (mycophenolate mofetil + glucocorticoids + cyclophosphamide) and were followed for an average of 48 months. There was no difference in the time to renal flare (HR, 0.75; 95% CI, 0.33–1.71 for mycophenolate compared with azathioprine). Adverse reactions were similar among the groups.56
Cutaneous lupus erythematosus. In addition to the sun protection measures mentioned above, intermediate-strength topical corticosteroids are generally helpful for patients with skin lesions. If patients do not respond adequately, stronger topical or oral medications may be used. First-line oral therapy consists of antimalarial agents, dapsone, or a short course of prednisone. If these treatments fail, then treatment can move on to isotretinoin or gold compounds. For more severe, resistant cases, methotrexate, cyclophosphamide, cyclosporine, or long-term corticosteroids can be tried. Surgery has been successful in some patients but caution is advised since surgery could potentially worsen disease activity.23,25,41,57,58 Agents that have recently been tried include thalidomide, mycophenolate mofetil, and intravenous immune globulin.58 Controlled trials are needed to determine the place of these agents in therapy.
Tacrolimus and pimecrolimus have also shown promise in treating skin lesions. Tacrolimus when compared to clobetasol showed a decrease in side effects with a similar efficacy profile.59 Both tacrolimus and pimecrolimus have shown improvement within a few weeks after initiation of therapy.59 Tacrolimus showed improvement in photosensitive rash, and pimecrolimus showed improvement in cutaneous lesions.59 Both medications also appear efficacious in subacute cutaneous lupus erythematosus. For discoid lupus, pimecrolimus appears to be more effective than tacrolimus.59 The main issue regarding these medications is that they have not been compared to other agents in a controlled manner. Controlled studies are needed to determine what role these agents may play in treating cutaneous symptoms.59
Neuropsychiatric lupus. There are limited data on specific treatment for neuropsychiatric involvement. Treatment usually focuses on the psychiatric symptoms rather than on treating the lupus (eg, anticonvulsants to treat seizures or antidepressants for patients with depressive symptoms). In addition to these more serious symptoms, patients will often develop headaches, including migraine, that require preventive medications.23,25,41,60 There is some evidence to suggest that rituximab may be useful in these patients as well, but controlled trials are needed to confirm this.61
One randomized controlled trial has been conducted comparing cyclophosphamide and methylprednisolone for the treatment of neuropsychiatric symptoms in patients with lupus.60,62 A statistically significant difference was seen between the groups with 18 of 19 patients in the cyclophosphamide group compared with 6 of 13 patients in the methylprednisolone group responding at 24 months (RR, 2.05; 95% CI, 1.13–3.73). Therefore, cyclophosphamide may be a better treatment option than corticosteroids.60,62 A risk/benefit analysis is needed before recommending cyclophosphamide in individual patients, due to the significant risk of adverse reactions.
Drug-induced lupus. Treatment of DILE is primarily withdrawal of the offending agent. Symptoms will generally start to resolve within a few days to weeks after discontinuation. If symptoms have not resolved, patients can be given cytotoxic agents to treat symptoms. Corticosteroids should be reserved for patients with organ damage. Patients who do not have complete resolution of symptoms should be worked up for development of idiopathic SLE, since some medications may just expose an underlying case rather than causing DILE.8–10
Several agents have recently been or are currently being evaluated for safety and efficacy in lupus. Many of these medications have failed to show a difference when compared to placebo or standard therapy, while others are still in the early stages of clinical trial testing. Leflunomide has shown some promising results in clinical trials.63,64 Rituximab is another agent that has some limited data to suggest that it may be beneficial in patients with SLE nephritis.25,61,65 Clinical trials with rituximab are currently underway or have reached completion, and will help to define its role in therapy.
Systemic lupus erythematosus is an autoimmune disorder that can affect several organ systems, including the skin, kidneys, and CNS. Better and earlier recognition of SLE and more effective treatments have significantly improved survival rates. Treatment is generally individualized, based on clinical presentation of the patient. The main nonpharmacologic management strategies are proper sun protection (eg, avoidance, protective clothing, and sunscreen with both UVA and UVB protection) and proper nutrition. Glucocorticoids, NSAIDs, cytotoxic/immunosuppressive agents, and antimalarials are used for generalized symptoms and patients with more chronic or severe symptoms. Lupus nephritis is one of the most common manifestations and is generally treated with a combination of cyclophosphamide and corticosteroids. Other disease manifestations may be treated with therapy targeting the specific condition, such as antipsychotic medications for psychiatric symptoms.
Dr Bernknopf is associate professor, Ferris State University, Kalamazoo, Mich. Dr Rowley is assistant professor, Ferris State University. Dr Bailey is professor, Ferris State University.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
1. Miah T, Hoque MA, Mahmood T, Tarafder BK. Clinical profile, management and outcome of lupus. Mymensingh Med J. 2008;17(suppl 2):S6–S11.
2. Jiménez S, Cervera R, Font J, Ingelmo M. The epidemiology of systemic lupus erythematosus. Clin Rev Allergy Immunol. 2003;25:3–11.
3. Bongu A, Chang E, Ramsey-Goldman R. Can morbidity and mortality of SLE be improved? Best Pract Res Clin Rheumatol. 2002;16:313–332.
4. Lazaro D. Elderly-onset systemic lupus erythematosus: prevalence, clinical course and treatment. Drugs Aging. 2007;24:701–715.
5. Amissah-Arthur MB, Gordon C. GPs have key role in shared care of patients with SLE. Practitioner. 2009;253:19–24.
6. Bae SC, Fraser P, Liang MH. The epidemiology of systemic lupus erythematosus in populations of African ancestry: a critical review of the "prevalence gradient hypothesis." Arthritis Rheum. 1998;41:2091–2099.
7. Crosslin KL, Wiginton KL. The impact of race and ethnicity on disease severity in systemic lupus erythematosus. Ethn Dis. 2009;19:301–307.
8. Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: an update on its dermatologic aspects. Lupus. 2009;18:935–940.
9. Vedove CD, Del Giglio M, Schena D, Girolomoni G. Drug-induced lupus erythematosus. Arch Dermatol Res. 2009;301:99–105.
10. Sarzi-Puttini P, Atzeni F, Capsoni F, Lubrano E, Doria A. Drug-induced lupus erythematosus. Autoimmunity. 2005;38:507–518.
11. Suh CH, Kim HA. Cytokines and their receptors as biomarkers of systemic lupus erythematosus. Expert Rev Mol Diagn. 2008;8:189–198.
12. Reidenberg MM. Aromatic amines and the pathogenesis of lupus erythematosus. Am J Med. 1983;75:1037–1042.
13. Petri M, Allbritton J. Hair product use in systemic lupus erythematosus: a case-control study. Arthritis Rheum. 1992;35:625–629.
14. Hess EV, Farhey Y. Etiology, environmental relationships, epidemiology, and genetics of systemic lupus erythematosus. Curr Opin Rheumatol. 1995;7:371–375.
15. Zulian F, Pluchinotta FR, Martini G, Da Dalt L, Zacchello G. Severe clinical course of systemic lupus erythematosus in the first year of life. Lupus. 2008;17:780–786.
16. McAlindon T. Update on the epidemiology of systemic lupus erythematosus: new spins on old ideas. Curr Opin Rheumatol. 2000;12:104–112.
17. Sánchez-Guerrero J, Liang MH, Karlson EW, Hunter DJ, Colditz GA. Postmenopausal estrogen therapy and the risk for developing systemic lupus erythematosus. Ann Intern Med. 1995;122:430–433.
18. Chen CJ, Lin KH, Lin SC, et al. High prevalence of immunoglobulin A antibody against Epstein-Barr virus capsid antigen in adult patient with lupus with disease flare: case control studies. J Rheumatol. 2005;32:44-47.
19. Ramos-Casals M, Brito-Zerón, Munñoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine. 2007;86:242–251.
20. Smith EL, Shmerling RH. The American College of Rheumatology criteria for the classification of systemic lupus erythematosus: strengths, weaknesses, and opportunities for improvement. Lupus. 1999;8:586–595.
21. Weening JJ, D'Agati VD, Schwartz MM, et al, on behalf of the International Society of Nephrology and Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15:241–250.
22. Aranow C, Ginzler EM. Epidemiology of cardiovascular disease in systemic lupus erythematosus. Lupus. 2000;9:166–169.
23. Madhok R, Wu O. Systemic lupus erythematosus. Clin Evid. 2009;7:1123.
24. Gladman D, Urowitz M. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum.1999;42:1785–1796.
25. Bertsias G, Ioannidis JPA, Boletis J, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis. 2008;67:195–205.
26. Haq I, Isenberg DA. How does one assess and monitor patients with systemic lupus erythematosus in daily clinical practice? Best Pract Res Clin Rheumatol. 2002;16:181–194.
27. Petri M. Monitoring systemic lupus erythematosus in standard clinical care. Best Pract Res Clin Rheumatol. 2007;21:687–697.
28. Ghaussy NO, Sibbitt W, Bankhurst AD, Qualls CR. Cigarette smoking and disease activity in systemic lupus erythematosus. J Rheumatol. 2003;30:1215–1221.
29. Benlysta® [prescribing information]. Rockville, MD: Human Genome Sciences, Inc., March 2011. Available at: http://www.hgsi.com/images/Benlysta/pdf/benlysta_pi.pdf. Accessed March 29, 2011.
30. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008;118:1894–1909.
31. Alarcon GS, McGwin G, Bertoli AM, et al, for the LUMINA Study Group. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis. 2007;66:1168–1172.
32. Ruiz-Irastorza G, Egurbide MV, Pijoan JI, et al. Effects of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15:577–583.
33. Shapiro T, Goldberg D. Chemotherapy of protozoal infections. In: Brunton L, Lazo J, Parker K, eds. Goodman & Gillman's The Pharmacological Basis of Therapeutics. 11th edition. New York: McGraw Hill, 2006:1032–1041.
34. Marmor MF, Carr RE, Easterbrook M, Farjo AA, Mieler WF, for the American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology. 2002;109:1377–1382.
35. Parker BJ, Bruce IN. High dose methylprednisolone therapy for the treatment of severe systemic lupus erythematosus. Lupus. 2007;16:387–393.
36. Mok CC. Therapeutic options for resistant lupus nephritis. Semin Arthritis Rheum. 2006;36:71–81.
37. Bansal VK, Beto JA. Treatment of lupus nephritis: a meta-analysis of clinical trials. Am J Kidney Dis. 1997;29:193–199.
38. Houssiau F. Thirty years of cyclophosphamide: assessing the evidence. Lupus. 2007;16:212–216.
39. Kuiper-Geertsma DG, Derksen RHWM. Newer drugs for the treatment of lupus nephritis. Drugs. 2003;63:167–180.
40. Navaneethan SD, Viswanathan G, Strippoli GFM. Treatment options for proliferative lupus nephritis: an update of clinical trial evidence. Drugs. 2008;68:2095–2104.
41. Bertsias G, Gordon C, Boumpas DT. Clinical trials in systemic lupus erythematosus (SLE): lessons from the past as we proceed to the future–the EULAR recommendations for the management of SLE and the use of end-points in clinical trials. Lupus. 2008;17:437–442.
42. Petri M, Stohl W, Chatham W, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008:58:2453–2459.
43. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009:61:1168–1178.
44. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009:61:1143–1151.
45. Navarra SV, Guzmán RM, Gallagher AE, et al; BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2001;377:721–731.
46. Human genome sciences and GlaxoSmithKline announce full presentation at EULAR of BLISS-76 phase 3 study results for Benlysta in systemic lupus erythematosus. 17 June 2010. Available at: http://www.hgsi.com/latest/human-genome-sciences-and-glaxosmithkline-announce-full-presentation-at-eular-of-bliss-76-phase-3-study-results-for-benlysta-in-systemic-lupus-erythema-4.html. Accessed March 29, 2011.
47. Flanc RS, Roberts MA, Strippoli GFM, Chadban SJ, Kerr PG, Atkins RC. Treatment for lupus nephritis. Cochrane Database Syst Rev. 2004:CD002922.
48. Rheumatrex [prescribing information]. Fort Lee, NJ: DAVA Pharmaceuticals, July 2009. Available at: http://www.rheumatrex.info/pdf/RheumatrexPackageInsert.pdf. Accessed July 20, 2010.
49. CellCept [prescribing information]. South San Francisco, CA: Genentech, February 2010. Available at: http://www.gene.com/gene/products/information/cellcept/pdf/pi.pdf. Accessed July 20, 2010.
50. Imuran [prescribing information]. San Diego, CA: Prometheus Laboratories, April 2009. Available at: http://www.prometheuslabs.com/products_therapeutics_imuran.asp. Accessed July 20, 2010.
51. Flanc RS, Roberts MA, Strippoli GFM, Chadban SJ, Kerr PG, Atkins RC. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis. 2004;43:197–208.
52. Zhu B, Chen N, Lin Y, et al. Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2007;22:1933–1942.
53. Kamanamool N, McEvoy M, Attia J, Ingsathit A, Ngamjanyaporn P, Thakkinstian A. Efficacy and adverse events of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: systematic review and meta-analysis. Medicine. 2010;89:227–235.
54. Mak A, Cheak AAC, Tan JYS, Su HC, Ho RCM, Lau CS. Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta-analysis and meta-regression. Rheumatology. 2009;48:944–952.
55. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis. Lupus. 2010;19:703–710.
56. Houssiau FA, Cruz DD, Sangle S, et al; the MAINTAIN Nephritis Trial Group. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69:2083–2089.
57. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for cutaneous lupus erythematosus: American Academy of Dermatology. J Am Acad Dermatol. 1996;34(5 Pt 1):830–836.
58. Callen JP. Update on the management of cutaneous lupus erythematosus. Br J Dermatol. 2004;151:731–736.
59. Tzellos TG, Kouvelas D. Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation. Eur J Clin Pharmacol. 2008;64:337–341.
60. Hermosillo-Romo D, Brey RL. Neuropsychiatric involvement in systemic lupus erythematosus. Curr Rheumatol Rep. 2002;4:337–344.
61. Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA. Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus. 2009;18:767–776.
62. Trevisani VFM, Castro AA, Ferreira Neves Neto JJFNN, Atallah AN. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database Syst Rev. 2006:CD002265.
63. Zhang FS, Nie YK, Jin XM, Yu HM, Li YN, Sun Y. The efficacy and safety of leflunomide therapy in lupus nephritis by repeat kidney biopsy. Rheumatol Int. 2009;29:1331–1335.
65. Tam LS, Li EK, Wong CK, Lam CWK, Szeto CC. Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus. Lupus. 2004;13:601–604.
66. Ramos-Casals M, Diaz-Lagares C, Soto-Cardenas MJ, et al. Rituximab therapy in lupus nephritis: current clinical evidence. Clin Rev Allergy Immunol. 2011;40:159–169.