Management of systemic lupus erythematosus (SLE) often depends on disease severity and disease manifestations, [8] although hydroxychloroquine has a central role for long-term treatment in all SLE patients. The LUMINA (Lupus in Minorities: Nature versus Nurture) study and other trials have offered evidence of a decrease in flares and prolonged life in patients given hydroxychloroquine, making it the cornerstone of SLE management. [104]
In general, cutaneous manifestations, musculoskeletal manifestations, and serositis represent milder disease, which may wax and wane with disease activity. These are often controlled with nonsteroidal anti-inflammatory drugs (NSAIDS) or low-potency immunosuppression medications beyond hydroxychloroquine and/or short courses of corticosteroids. More prolonged steroid use is generally reserved for patients with involvement of vital organs. For example, central nervous system involvement and diffuse proliferative renal disease must be recognized as more severe disease manifestations, and these are often treated with more aggressive immunosuppression. Evidence suggests a relative undertreatment of SLE patients with end-stage renal disease (ESRD), because the extent of lupus activity may be underestimated.
EULAR recommendations
In 2007, the European League Against Rheumatism (EULAR) released recommendations for the treatment of SLE. [61] In patients with SLE without major organ manifestations, glucocorticoids and antimalarial agents may be beneficial. [61] NSAIDs may be used for short periods in patients at low risk for complications from these drugs. Consider immunosuppressive agents (eg, azathioprine, mycophenolate mofetil, methotrexate) in refractory cases or when steroid doses cannot be reduced to levels for long-term use. [106]
EULAR recommendations for the management of SLE with neuropsychiatric manifestations support the evaluation and treatment of these symptoms in the same way as they are evaluated and treated in patients without SLE; if symptoms persist, management of these symptoms as an extension of SLE should be considered. [83, 61] For example, in patients with neuropsychiatric manifestations that may have an inflammatory etiology, immunosuppressive agents may be considered. [61]
Other guidelines
In 2009, an American College of Rheumatology (ACR) Task Force generated a quality indicator set. [107] In 2012, the ACR published “ Guidelines for the Screening, Diagnosis, Treatment and Monitoring of Lupus Nephritis in Adults,” as well as an evidence report for lupus nephritis. These and other guidelines are available at the ACR's Clinical Practice Guidelines Web site.
Adjunctive therapies
Vitamin D insufficiency and deficiency are more common in patients with SLE than in the general population. [108]Vitamin D supplementation may decrease disease activity and improve fatigue. [109, 110] In addition,supplementation may improve endothelial function, which may reduce cardiovascular disease. [111, 112, 113]
No diet-based treatment of SLE has been proven effective. Patients with SLE should be reminded that activity may need to be modified as tolerated. Specifically, stress and physical illness may precipitate SLE flares. Additionally, persons with SLE should wear sunscreen and protective clothing or avoid sun exposure to limit photosensitive rash or disease flares.
Consultations
The multisystemic nature of SLE often requires involvement of consultants, depending on the organ system involved. Consultation with any of the following specialists may be necessary:
- Rheumatologist
- Infectious disease specialist
- Neurologist
- Pulmonologist
- Cardiologist
- Gastroenterologist
- Nephrologist
- Dermatologist
- Hematologist
- High-risk obstetrician
Biologic DMARD Therapy
Belimumab
The monoclonal antibody belimumab (Benlysta), a B-lymphocyte stimulator–specific inhibitor, has been found to reduce disease activity and possibly decrease the number of severe flares and steroid use in patients with SLE when used in combination with standard therapy. [114] In March, 2011, the US Food and Drug Administration (FDA) approved the use of belimumab in combination with standard therapies (including steroids, nonbiologic DMARDS [eg, hydroxychloroquine, azathioprine, methotrexate]) to treat active autoantibody-positive SLE. [115] In July 2017, a subcutaneous (SC) formulation was approved that allows patients to self-administer a once-weekly dose. [116]
Patients of African-American or African descent did not show significant responses to belimumab in phase III post-hoc analysis, but those studies were not powered to assess for this effect; in a phase II trial, blacks had a greater treatment response. These results indicate that the benefits of belimumab in SLE patients remain inconclusive and that further investigation is needed. Patients with severe active lupus nephritis or CNS lupus or patients previously treated with other biologics or cyclophosphamide have been excluded from participation in early trials.
The SLE Responder Index (SRI) is a tool that was developed following phase II trials and is composed of the following scores [117] :
- SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment– Systemic Lupus Erythematosus Disease Activity Index)
- BILAG (British Isles Lupus Assessment Group)
- PGA (physician global assessment)
SRI response is defined by the following[117] :
- A 4-point or greater reduction in the SELENA-SLEDAI score
- No new BILAG A or no more than 1 new BILAG B domain score
- No deterioration from baseline in the PGA by 0.3 or more points.
A multinational phase III study (BLISS-52) that evaluated the efficacy and safety of IV belimumab, in 867 patients with a minimum SELENA-SLEDAI score of 6, reported that patients given belimumab had significantly higher SRI scores at 52 weeks than did those given placebo. [118]All groups had similar rates of adverse events.
Similarly, a phase III trial of 819 SLE patients who were positive for either antinuclear antibody or anti–double-stranded DNA at baseline screening found that IV belimumab at 10 mg/kg plus standard therapy resulted in a significantly greater SRI score (43.2%) than placebo (33.5%) at 1 year (those who received belimumab 1 mg/kg plus standard therapy had a 40.6% response rate). [119] Overall, the addition of belimumab to standard therapy reduced SLE disease activity and severe flares, and the medication was well tolerated.[119]
Approval for SC belimumab was based on the BLISS-SC phase III study (n=839), which documented reduction in disease activity at week 52 in patients receiving belimumab plus standard of care, compared with those receiving placebo plus standard of care. SRI response with belimumab versus placebo was 61.4% vs 48.4%, respectively (P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171 days vs 118 days; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% vs 11.9%; P = 0.0732), compared with placebo. [120]
Rituximab
B-cell depletion with rituximab (Rituxan) has been used successfully for rheumatoid arthritis, but studies have shown mixed results for the treatment of SLE. An open study using rituximab showed excellent results as rescue therapy for patients with active SLE who were unresponsive to standard immunosuppressant therapy.
There have also been case reports of patients with severe refractory SLE in which off-label use of rituximab showed benefits with tolerable safety profiles.[122, 123, 124] For example, in a retrospective study of 115 patients with severe or refractory SLE, 40% of patients had a complete response and 27% had a partial response, as measured by BILAG scores recorded 6 months after the first rituximab treatment. [125]
However, three placebo-controlled studies, including the Exploratory Phase II/III SLE Evaluation of Rituximab [EXPLORER] trial and the Lupus Nephritis Assessment with Rituximab [LUNAR] trial,[126, 127] failed to show an overall significant response. Despite the negative results in these trials, rituximab continues to be used to treat patients with severe SLE disease that is refractory to standard therapy.
Pharmacologic agents targeting specific pathways such as cytokines and complement, as well as combinations of rituximab with costimulatory inhibition with anti-CD4OL or CTLA-41g, may prove to be more effective in treating SLE.
Approach Considerations
Management of systemic lupus erythematosus (SLE) often depends on disease severity and disease manifestations, [8] although hydroxychloroquine has a central role for long-term treatment in all SLE patients. The LUMINA (Lupus in Minorities: Nature versus Nurture) study and other trials have offered evidence of a decrease in flares and prolonged life in patients given hydroxychloroquine, making it the cornerstone of SLE management. [104]
In general, cutaneous manifestations, musculoskeletal manifestations, and serositis represent milder disease, which may wax and wane with disease activity. These are often controlled with nonsteroidal anti-inflammatory drugs (NSAIDS) or low-potency immunosuppression medications beyond hydroxychloroquine and/or short courses of corticosteroids. More prolonged steroid use is generally reserved for patients with involvement of vital organs. For example, central nervous system involvement and diffuse proliferative renal disease must be recognized as more severe disease manifestations, and these are often treated with more aggressive immunosuppression. Evidence suggests a relative undertreatment of SLE patients with end-stage renal disease (ESRD), because the extent of lupus activity may be underestimated. [105]
EULAR recommendations
In 2007, the European League Against Rheumatism (EULAR) released recommendations for the treatment of SLE. [61] In patients with SLE without major organ manifestations, glucocorticoids and antimalarial agents may be beneficial. [61] NSAIDs may be used for short periods in patients at low risk for complications from these drugs. Consider immunosuppressive agents (eg, azathioprine, mycophenolate mofetil, methotrexate) in refractory cases or when steroid doses cannot be reduced to levels for long-term use. [106]
EULAR recommendations for the management of SLE with neuropsychiatric manifestations support the evaluation and treatment of these symptoms in the same way as they are evaluated and treated in patients without SLE; if symptoms persist, management of these symptoms as an extension of SLE should be considered. [83, 61] For example, in patients with neuropsychiatric manifestations that may have an inflammatory etiology, immunosuppressive agents may be considered. [61]
Other guidelines
In 2009, an American College of Rheumatology (ACR) Task Force generated a quality indicator set. [107] In 2012, the ACR published “ Guidelines for the Screening, Diagnosis, Treatment and Monitoring of Lupus Nephritis in Adults,” as well as an evidence report for lupus nephritis. These and other guidelines are available at the ACR's Clinical Practice Guidelines Web site.
Adjunctive therapies
Vitamin D insufficiency and deficiency are more common in patients with SLE than in the general population. [108]Vitamin D supplementation may decrease disease activity and improve fatigue. [109, 110] In addition,supplementation may improve endothelial function, which may reduce cardiovascular disease. [111, 112, 113]
No diet-based treatment of SLE has been proven effective. Patients with SLE should be reminded that activity may need to be modified as tolerated. Specifically, stress and physical illness may precipitate SLE flares. Additionally, persons with SLE should wear sunscreen and protective clothing or avoid sun exposure to limit photosensitive rash or disease flares.
Consultations
The multisystemic nature of SLE often requires involvement of consultants, depending on the organ system involved. Consultation with any of the following specialists may be necessary:
- Rheumatologist
- Infectious disease specialist
- Neurologist
- Pulmonologist
- Cardiologist
- Gastroenterologist
- Nephrologist
- Dermatologist
- Hematologist
- High-risk obstetrician
Biologic DMARD Therapy
Belimumab
The monoclonal antibody belimumab (Benlysta), a B-lymphocyte stimulator–specific inhibitor, has been found to reduce disease activity and possibly decrease the number of severe flares and steroid use in patients with SLE when used in combination with standard therapy. [114] In March, 2011, the US Food and Drug Administration (FDA) approved the use of belimumab in combination with standard therapies (including steroids, nonbiologic DMARDS [eg, hydroxychloroquine, azathioprine, methotrexate]) to treat active autoantibody-positive SLE. [115] In July 2017, a subcutaneous (SC) formulation was approved that allows patients to self-administer a once-weekly dose. [116]
Patients of African-American or African descent did not show significant responses to belimumab in phase III post-hoc analysis, but those studies were not powered to assess for this effect; in a phase II trial, blacks had a greater treatment response. These results indicate that the benefits of belimumab in SLE patients remain inconclusive and that further investigation is needed. Patients with severe active lupus nephritis or CNS lupus or patients previously treated with other biologics or cyclophosphamide have been excluded from participation in early trials.
The SLE Responder Index (SRI) is a tool that was developed following phase II trials and is composed of the following scores [117] :
- SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment– Systemic Lupus Erythematosus Disease Activity Index)
- BILAG (British Isles Lupus Assessment Group)
- PGA (physician global assessment)
SRI response is defined by the following[117] :
- A 4-point or greater reduction in the SELENA-SLEDAI score
- No new BILAG A or no more than 1 new BILAG B domain score
- No deterioration from baseline in the PGA by 0.3 or more points.
A multinational phase III study (BLISS-52) that evaluated the efficacy and safety of IV belimumab, in 867 patients with a minimum SELENA-SLEDAI score of 6, reported that patients given belimumab had significantly higher SRI scores at 52 weeks than did those given placebo. [118]All groups had similar rates of adverse events.
Similarly, a phase III trial of 819 SLE patients who were positive for either antinuclear antibody or anti–double-stranded DNA at baseline screening found that IV belimumab at 10 mg/kg plus standard therapy resulted in a significantly greater SRI score (43.2%) than placebo (33.5%) at 1 year (those who received belimumab 1 mg/kg plus standard therapy had a 40.6% response rate). [119] Overall, the addition of belimumab to standard therapy reduced SLE disease activity and severe flares, and the medication was well tolerated.[119]
Approval for SC belimumab was based on the BLISS-SC phase III study (n=839), which documented reduction in disease activity at week 52 in patients receiving belimumab plus standard of care, compared with those receiving placebo plus standard of care. SRI response with belimumab versus placebo was 61.4% vs 48.4%, respectively (P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171 days vs 118 days; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% vs 11.9%; P = 0.0732), compared with placebo. [120]
Rituximab
B-cell depletion with rituximab (Rituxan) has been used successfully for rheumatoid arthritis, but studies have shown mixed results for the treatment of SLE. An open study using rituximab showed excellent results as rescue therapy for patients with active SLE who were unresponsive to standard immunosuppressant therapy. [121]
There have also been case reports of patients with severe refractory SLE in which off-label use of rituximab showed benefits with tolerable safety profiles.[122, 123, 124] For example, in a retrospective study of 115 patients with severe or refractory SLE, 40% of patients had a complete response and 27% had a partial response, as measured by BILAG scores recorded 6 months after the first rituximab treatment. [125]
However, three placebo-controlled studies, including the Exploratory Phase II/III SLE Evaluation of Rituximab [EXPLORER] trial and the Lupus Nephritis Assessment with Rituximab [LUNAR] trial,[126, 127] failed to show an overall significant response. Despite the negative results in these trials, rituximab continues to be used to treat patients with severe SLE disease that is refractory to standard therapy.
Pharmacologic agents targeting specific pathways such as cytokines and complement, as well as combinations of rituximab with costimulatory inhibition with anti-CD4OL or CTLA-41g, may prove to be more effective in treating SLE. [128]
Emergency Department Management
Acute emergencies in patients with systemic lupus erythematosus (SLE) include the following:
- Severe neurologic involvement
- Systemic vasculitis
- Profound thrombocytopenia with a thrombotic thrombocytopenia (TTP)–like syndrome
- Rapidly progressive glomerulonephritis
- Diffuse alveolar hemorrhage [129]
These conditions may be treated with high-dose intravenous steroids and cytotoxic therapy such as cyclophosphamide. Strokes, acute myocardial infarctions, and pulmonary emboli occurring as complications of SLE are managed in the same way as they are in patients without SLE. In patients who present with fever, it may be necessary to limit immunosuppression to steroids and to empirically treat for an infection until culture results have been received.
In rare cases, diffuse alveolar hemorrhage may require plasma exchange, or profound steroid-refractory thrombocytopenia may require therapy with intravenous immunoglobulin (IVIG). Catastrophic antiphospholipid antibody syndrome also requires aggressive acute management.
For more information, see the Medscape Reference article Antiphospholipid Syndrome.
Hospitalization
Fever in patients with systemic lupus erythematosus (SLE) is grounds for hospital admission because of the difficulty of distinguishing a disease flare from infection in these immunocompromised hosts. Patients with SLE are often complement deficient and functionally asplenic; therefore, they are at particular risk for infections with encapsulated organisms. For example, meningococcemia in young females with lupus may be catastrophic.
Although it is known that chronically low complement levels and functional asplenia may result in a low level of susceptibility to infection, it is not known to what degree. [130, 131] Overall, it is likely that the primary reason patients with SLE die of infections is immunosuppressive medications.Stress-dose steroid protocols should be used in patients who are receiving maintenance corticosteroids when they are admitted with infectious or perioperative stress.
Central nervous system lupus with depressed consciousness or alveolar hemorrhage may prompt transfer to an intensive care unit and consideration of protective intubation. Thrombotic thrombocytopenic purpura and catastrophic antiphospholipid antibody syndrome should prompt transfer to a center capable of offering plasma exchange therapy.
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