Clinical Updates: Systemic Lupus Erythematosus
Disease Overview
Systemic lupus erythematosus (SLE) is an autoimmune disease that can cause inflammation and tissue damage. Disease severity can range from mild to life threatening, and symptoms vary between individuals, can change over time, and are similar to symptoms of other diseases, making it a difficult disease to diagnose.1 The most common symptoms of SLE are skin rashes, arthritis, edema of the feet and around the eyes, extreme fatigue, and low-grade fevers.2 Although the direct cause of SLE is unknown, the disease is characterized by dysregulation of innate and adaptive immune pathways and the development of antinuclear antibodies.1,2
As one of the most common forms of lupus, SLE accounts for about 70% of the 1.5 million individuals in the United States with a form of lupus.3 While there are no recent incidence estimates available for SLE in the United States,2 updated data are currently being collected.1
Age and race/ethnicity significantly contribute to an individual’s risk for SLE. Patients most commonly develop SLE between age 15 and 44 years.2,3 The main risk factor for developing SLE is sex, as women account for 90% of individuals with SLE.3,4 In the United States, the estimated prevalence of SLE is 100 per 100,000 in White women and 400 per 100,000 in African-American women.5 In general, lupus is more common in African Americans, Hispanics/Latinos, Asians, Native Americans, Native Hawaiians, and Pacific Islanders, compared with the White population.2,4
Genetics also play a role in the risk for SLE. Individuals who have relatives with lupus have a 5% to 13% greater chance of developing lupus.4 However, if a mother has lupus, her child only has about a 5% chance of developing lupus.4
Diagnosis
A diagnosis of SLE is made based upon a combination of the following factors: (1) symptom assessment, (2) physical examination, (3) radiograph findings, and (4) laboratory findings.2 Making an SLE diagnosis is challenging, as many of the symptoms often overlap with other disease states.2 Signs and symptoms of SLE include fatigue, skin rash, fever, and pain or edema of the joints. SLE is often experienced in flares, where the disease relapses and remits over the course of the patient’s life.2 Additional symptoms include sensitivity to the sun, oral ulcers, arthritis, psychosis, seizures, blood and immunological abnormalities, and damage to other organs including the lungs, heart, and kidneys.2
The European League Against Rheumatism and the American College of Rheumatology have developed specific criteria to help classify SLE.6 The criteria include, but are not limited to, leukopenia, malar rash, antinuclear antibodies, fever, and thrombocytopenia.6 SLE should be diagnosed in patients who score 10 or more using the classification system.6
The direct causes of SLE are unknown, but it is believed to be a combination of internal and external factors, including hormones, genetics, and the environment.2,7 Researchers have analyzed the role of estrogen in SLE, as 9 out of 10 patients with lupus are women.4 To date, no connection between estrogen and SLE has been made.7
There are more than 50 genes associated with SLE, and while not directly tied to causing lupus, they are found more frequently in individuals with SLE.7 Most researchers believe that an environmental agent, randomly encountered by the person who develops lupus, triggers the disease. The specific environmental trigger(s) have not yet been specifically labelled; the most common causes are ultraviolet light, infections, and exposure to silica dust.7 Other environmental triggers include sulfonamide medications, sun-sensitizing tetracyclines, penicillin, exhaustion, and physical or emotional stressors.7
Treatment Options
SLE is a chronic disease that does not have a cure. The goals of treatment are to suppress the overactive immune system, prevent flares, and induce remission, thereby preventing permanent organ damage.8 Current treatment for SLE includes antimalarials, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and immunosuppressive agents.9
Antimalarials
Antimalarials have been used the longest for the treatment of SLE, and hydroxychloroquine (HCQ) is recommended for all patients with SLE unless there is a strong contraindication.9,10 Antimalarials work by inhibiting phagosomes, which inhibit toll-like receptor (TLR) activation and downregulates IFN-.9 HCQ is proven to improve survival and prevent end-organ damage over the long term.10 HCQ is well studied and has shown benefit for reducing cardiovascular and thrombotic risk , supporting a protective effect on bone mineral density, and a positive effect on pregnancy outcomes.11
Glucocorticosteroids
Glucocorticosteroids are another well-established treatment for SLE. They work by inhibiting B-cell and T-cell responses, as well as inhibiting NF-B activity to affect monocyte and neutrophil function.9 Long-term use of glucocorticosteroids can result in permanent organ damage, causing an increased risk of morbidity, as well as increase the risk for cataracts, osteoporosis and fractures, and coronary artery disease.12
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are prescribed to help control pain and decrease inflammation in SLE.13 NSAIDs work by blocking COX-1 and COX-2 enzymes; COX-2 (selective) inhibitors selectively target a protein that causes joint inflammation.13 Use of both selective and nonselective NSAIDs help treat SLE.13
Systemic Inflammation-Targeting Immunosuppressants
Immunosuppressants that can treat SLE include azathioprine (AZA; Imuran), mycophenolate mofetil (MMF; Cellcept), methotrexate (MTX; Rheumatrex), cyclophosphamide (CYC; Cytoxan), cyclosporine A (CsA; Neoral, Sandimmune, Gengraf), leflunomide (Arava), and rituximab (Rituxan). AZA, MMF, and MTX are steroid-sparing agents and may allow for lower concomitant doses of glucocorticosteroids.14
Azathioprine
AZA is a purine analog that is metabolized in vivo to its active form, mercaptopurine, which inhibits DNA synthesis and prevents immune cell proliferation.9 AZA decreases joint damage and improves lupus symptoms affecting the liver and kidneys.14 The expected time to effect of AZA is about 6 to 12 weeks, as it is a slow-onset medication.14 AZA is available orally and has fewer adverse effects than other immunosuppressants; the most common adverse effects are nausea, vomiting, and diarrhea. Blood tests are required to monitor white blood cells, platelets, and red blood cells.14
Mycophenolate mofetil
MMF is the medication of choice for maintenance treatment of SLE.15 Like AZA, MMF is also a prodrug. The active form, mycophenolic acid, inhibits inosine monophosphate dehydrogenase, which controls an essential step for lymphocyte DNA synthesis.9 MMF is typically prescribed to patients with SLE and kidney disease.14 The most common adverse effects of MMF are nausea, vomiting, and diarrhea; headache, dizziness, sleeplessness, and tremors are also possible.14
Methotrexate
MTX, a folic acid analog, inhibits dihydrofolate reductase to inhibit DNA and RNA synthesis.9 MTX is beneficial for patients with SLE and resistant arthritis and skin disease, but it does not help patients with SLE who have major organ involvement.9 MTX is a disease-modifying antirheumatic drug (DMARD), an immunosuppressant used to treat the pain and edema of arthritis from SLE.14
Cyclophosphamide
CTX, combined with a glucocorticosteroid, was the standard of treatment for lupus nephritis for many years.9 CTX is a cytotoxic medication, and due to its serious adverse effects, CTX is reserved for patients with SLE who have severe kidney damage and are refractory to other treatments.14
Cyclosporine
CsA blocks T-cell function and is prescribed for patients with SLE and kidney inflammation. Despite its use for lupus nephritis, CsA can cause kidney damage, so it is often reserved for patients who are refractory to other treatments.14
Leflunomide
Leflunomide is a DMARD, like MTX, and is used to treat SLE-related edema, pain, and stiffness.14 The medication works by blocking DNA formation in the body’s cells to prevent production of overactive immune cells.14 Leflunomide is often reserved for patients who are refractory to MTX.14
Immune Cell-Targeted Treatment
Rituximab
RTX is an anti-CD20 monoclonal antibody that depletes B cells from the peripheral blood. Because CD20 is not found on pro-B cells, pre-B cells, or plasma cells, it does not decrease immunoglobulin levels and spares T cells. It is less immunosuppressive than other agents.15 Results from the EXLORER and LUNAR trials—2 randomized, placebo-controlled, phase 3 trials—failed to meet their designated primary endpoints.16,17 Despite a lack of evidence and safety data, RTX is still widely used off label to treat SLE.
Belimumab
Belimumab (benlysta) is the only biologic agent to date that is licensed to treat SLE. The monoclonal antibody is a B-lymphocyte stimulator-specific inhibitor and works by inhibiting B-cell activating factor (BAFF).15,18 Two phase 3 clinical trials, BLISS-52 and BLISS-76, studied the effects of belimumab in patients with severe active SLE.19 Both studies demonstrated a significant improvement in the disease, as well as a reduction of flares and steroid use.19 Belimumab, which is administered intravenously, is generally well tolerated. Participants in clinical trials had experienced adverse events and discontinuation at the same rate as placebo.9 Belimumab is indicated for the treatment of SLE in children as young as age 5 years.18
Adjuvant Treatment
Intravenous Immunoglobulins (IVIGs)
IVIGs are prescribed for patients with concomitant SLE and an active infection or for patients who cannot receive traditional treatment. The use of purified IVIGs is still considered experimental.15
Therapeutic Plasma Exchange (TPE)
TPE is used to remove pathological substances from the blood and replace deficient plasma components via a filtration technique.15 This treatment is used when other therapies have failed or if the patient develops leukopenia and psychosis.15
Immunoadsorption (IAS)
IAS is an extracorporeal treatment that clears nearly all circulating immunoglobulin G and immune complexes without removing plasma proteins.15 IAS can be prescribed to patients who have contraindications to standard treatment, are pregnant, or have treatment-refractory SLE. However, additional evidence is required to determine the exact clinical use of IAS in the subsets of SLE manifestations.15 Researchers conducting a long-term observational study of 16 patients with severe SLE and renal disease found that IAS significantly reduced proteinuriea and improved disease activity.20 At the 3-month follow-up, proteinuria had decreased from 6.7 g/d at baseline to 4.3 g/d. At the 12-month follow-up, proteinuria had decreased even further to 2.9 g/d.20
Emerging Treatments
Targeting B-Cell Receptor Signaling
B-cell receptor signaling is an important component of creating and maintaining autoimmunity.15 Researchers theorize that CD22 activity may inhibit B-cell receptor signaling. However, epratuzumab, an anti-CD22 monoclonal antibody, showed no benefit over standard therapy in two phase 3, randomized, double-blind, placebo-controlled trials.21
Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT)
The JAK/STAT pathway controls signal transduction of more than 50 cytokines and growth factors, which play a role in the pathology of SLE.22 Baricitinib, which targets JAK1 and JAK2, demonstrated benefit compared with the standard of treatment for patients with highly active SLE and skin and joint symptoms.23 A phase 3 clinical trial to evaluate safety and efficacy is currently recruiting.24
Type 1 Interferon
The pathophysiology of SLE is impacted by IFN-activated genes.15 Rontalizumab and anifrolumab, 2 monoclonal antibodies, demonstrated positive effects in patients with SLE and have the potential for playing an important role in the development of precision medicine for SLE.15
Chimeric Antigen Receptor (CAR) T-Cell Therapy
CAR T-cell therapy, which is used mostly for the treatment of B-cell malignancies, may be useful for treating SLE. In mice, CD-19-targeted CAR T-cells decreased the level of B-cells.25 In another study, the researchers targeted the BAFF receptor with CAR T-cells and found that CAR T-cells can protect against lymphoma and leukemia.26 Utilizing anti-BAFF treatments in SLE would be a novel treatment approach.15
Flares in SLE
SLE flares, which are defined as a worsening of symptoms and increased feelings of sickness, occur following a trigger. Triggers are patient-specific, but common triggers include overworking, stress, sun exposure, fluorescent or halogen light exposure, infection, injury, discontinuation of SLE medications, and other medications.2,27 SLE flares are often preceded by warning signs, which allow patients to detect the flares early and seek treatment. The warning signs include increased fatigue, pain, rash, fever, stomachache, severe headache, and dizziness.2,27 Despite the ability to predict a flare, there is no way to tell whether the upcoming flare will be mild, moderate, or severe. Generally, patients with mild to moderate flares may experience a rash or increased joint pain, whereas patients with severe flares may experience damage to and increased fluid around body organs.27
Prognosis and Prevention
For patients with SLE without organ involvement, they can have an 80% to 90% chance of living a normal lifespan if they follow physician instructions, take medication as prescribed, and seek medical help when flares occur.28 In 2006, the most common causes of death in patients with SLE were infections, acute cardiovascular events caused by atherosclerosis, and cancer.29 While there is not yet a cure for lupus, the treatment goal of living in remission without flares is attainable.
As the causes of SLE are not fully understood, there is currently no definite way to prevent SLE. Once diagnosed, however, patients with SLE can reduce the risk of flares by understanding their triggers, seeing a physician regularly, reducing stress, limiting exposure to the sun and fluorescent or halogen lights, eating a healthy diet, getting enough sleep, exercising moderately, and relying on a support system.27
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16. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222-233. https://doi.org/10.1002/art.27233
17. Rovin BH, Furie R, Latinis K, et al; LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64(4):1215-1226. https://doi.org/10.1002/art.34359
18. GSK receives US approval of Benlysta for intravenous use in children with lupus aged five years and above. GlaxoSmithKline. News Release. April 26, 2019. Accessed January 18, 2021. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-us-approval-of-benlysta-for-intravenous-use-in-children-with-lupus-aged-five-years-and-above/
19. Strand V, Levy RA, Cervera R, et al; BLISS-51 and -76 Study Groups. Improvements in health-related quality of life with belimumab, a B-lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomised controlled BLISS trials. Ann Rheum Dis. 2014;73(5)838-844. https://doi.org/10.1136/annrheumdis-2012-202865
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23. A study of baricitinib (LY3009104) in participants with systemic lupus erythematosus (SLE). Clinicaltrials.gov. Updated November 21, 2018. Accessed January 18, 2021. Clinicaltrials.gov identifier: NCT02708095 https://clinicaltrials.gov/ct2/show/NCT02708095
24. A study of baricitinib in participants with systemic lupus erythematosus (SLE) (SLE-BRAVE-X). Clinicaltrials.gov. Updated January 7, 2021. Accessed January 18, 2021. Clinicaltrials.gov identifier: NCT03843125 https://clinicaltrials.gov/ct2/show/NCT03843125
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26. Qin H, Dong Z, Wang X, et al. CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. Sci Transl Med. 2019;11(511):eaaw9414. https://doi.org/10.1126/scitranslmed.aaw9414
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29. Doria A, Iaccarino L, Ghirardello A, et al. Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med. 2006;119(8):700-706. https://doi.org/10.1016/j.amjmed.2005.11.034
