LUPUS: A COMPLEX AUTOIMMUNE DISEASE
SALAM KADHIM, PhD
Salam Kadhim is a pharmaceutical scientist with experience in drug discovery and development of small molecule compounds, biologics, siRNA, and cannabinoids in the areas of oncology, HBV, cardiovascular, ocular, and neurodegenerative disorders.
Topic Overview
Systemic lupus erythematosus (SLE), or lupus, is a chronic, progressive autoimmune disorder in which the immune system attacks its own healthy tissues, causing widespread inflammation and tissue damage to multiple organ systems. Due to its heterogeneity, it has a significant impact on many dimensions of patients’ well-being, causing marked impairment in health- related quality of life. This course provides insights into the definition and types of lupus, clinical manifestations, laboratory screen measures for diagnosis as well as the currently available medications with their associated adverse effects. Furthermore, a gap analysis of the current treatment practices will be compared to the best practice to identify areas of improvement. Special topics in managing flares, during pregnancy, in pediatrics, risk factors, and patient counseling are also reviewed.
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Credits: 2 hours of continuing education credit
Type of Activity: Knowledge
Media: Internet/Home study Fee Information: $6.99
Estimated time to complete activity: 2 hours, including Course Test and course evaluation.
Release Date: June 10, 2023 Expiration Date: June 10, 2026
Target Audience: This educational activity is for pharmacists.
How to Earn Credit: From June 10, 2023, through June 10, 2026, participants must:
Read the “learning objectives” and “author and planning team disclosures;”
Study the section entitled “educational activity;” and
Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)
Credit for this course will be uploaded to CPE Monitor®.
Learning Objectives: Upon completing this educational activity, participants should be able to:
Provide insights into the definition and different types of lupus.
Describe clinical manifestations comprising systemic and specific symptoms of organ-system dysfunction associated with lupus.
Describe laboratory screen tests for diagnosis and classification criteria of lupus.
Describe current treatments in the management of lupus.
Discuss the current challenges and future directions in lupus treatment and management.
Disclosures
The following individuals were involved in developing this activity: Salam Kadhim, PhD, and Pamela Sardo, PharmD, BS. Salam Kadhim, PhD, was a senior scientist at Inmed Pharmaceuticals until July 1, 2022. Pamela Sardo, PharmD, BS, was an employee of Rhythm Pharmaceuticals until March 2022. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.
© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.
Introduction
Systemic lupus erythematosus is a chronic, complex autoimmune disease. It is the most common type of lupus. Lupus can develop in individuals from all population groups, but it is most prevalent among women. Lupus treatment is highly individualized and depends on symptom manifestations, organ involvement, disease severity, and patient response. These include pharmacological and nonpharmacological treatments and counseling for the lupus patient. An approach that treats the condition early, with sustained symptom management, can prevent organ damage, and the patient’s quality of life and long-term survival can be improved.
Overview of Lupus
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that manifests itself when the immune system attacks its own healthy tissues.1 This attack causes widespread inflammation and tissue damage affecting skin, joints, heart, lungs, kidneys, and blood vessels.1 Systemic lupus erythematosus is not curable so treatments will involve the management of symptoms and protection from organ injury.1,2
The prevalence of SLE has been estimated to be 30–50 per 100,000, equating to approximately 500,000 patients in Europe and 250,000 in the USA.2,3 The incidence and prevalence are higher in African Americans, Native American, Asian, and Hispanic/Latino patients who develop more severe disease with higher mortality than Caucasian patients.4–6 Systemic lupus erythematosus has a prominent female predominance, especially in women of childbearing age. The female-to-male ratio is as high as 13:1. It is only at 2:1 in children and the elderly.7,8 African-American women are about 3 times more likely to have lupus and suffer greater mortality compared to Caucasian women.9 Systemic lupus erythematosus often follows a characteristic pattern of relapse and remissions and typically develops over an extended period of time.10,11 The exact etiology of the disease is unknown; however, it is associated with a complex and multifactorial interaction of genetic, environmental, immunological, and hormonal factors.12,13
Definition and Pathogenesis of Lupus
Systemic lupus erythematosus is an inadequately defined chronic autoimmune disease involving multiple organs and biological processes. It displays a pleomorphic clinical course with a poorly understood pathogenesis.14,15 Lupus may be divided into different types:16
Systemic Lupus Erythematosus is the most common form of lupus.
Cutaneous lupus is a form of lupus that is limited to the skin.
Drug-induced lupus is a lupus-like disease caused by certain prescription drugs.
Neonatal lupus is a rare condition that affects infants of women who have lupus.
“Childhood lupus” in children affects the body in the same manner as adult lupus. Boys have a higher prevalence of lupus than males in adulthood. Childhood lupus affects certain organs, such as the kidneys, to a greater extent.
Autoantibody production is a central immunological disorder and one of the main contributing factors in the development of SLE. A wide spectrum of autoantibodies directed at self-antigens in the nucleus, cytoplasm, and cell membrane are characteristically present in more than 95% of patients with SLE.17 Anti-double stranded DNA (ds-DNA) and anti-Smith (anti-Sm) autoantibodies are unique to patients with SLE.17,18 Anti-dsDNA antibodies bind to a conserved nucleic acid determinant widely present on DNA, whereas, anti-Sm antibodies react with small nuclear ribonucleoprotein (snRNP).17 Anti- DNA antibodies show preferential deposition in the kidneys, indicating that these autoantibody-immune complexes are the main mediators of inflammation.19 The most remarkable feature of anti-DNA antibodies is their association with glomerulonephritis (inflammation and damage of the glomeruli, the filtration units of kidneys).20
Defective immune regulation of innate and adaptive arms of the immune system in SLE results in the loss of immune tolerance to self-antigens.21 Several abnormalities of the immune system contribute to the disease and
involve defective B cell suppression, excess T cell help, impaired phagocytic function, induction of polyclonal B cell activation, increased number of antibody-producing cells, hypergammaglobulinemia, autoantibody production, and immune complex formation.15 B cell activation is abnormal in patients with SLE, and their number is increased in peripheral blood at all stages of activation.17,22 T-cells are defective, and their aberration is evident by increased apoptosis and decreased number in peripheral blood of SLE patients.23,24 Excessive and uncontrolled T cell help plays a central role in differentiation and activation of autoantibody forming B cells and is the final common pathway.25 Furthermore, strong induction of proinflammatory type 1 Interferon pathway is recognized as the pivotal role of the innate immune system in lupus.26,27
Genome-wide association studies (GWAS) have confirmed the importance of genetic susceptibility to SLE associated with the immune response, endothelial function, and tissue response to injury.28,29 Linkage analyses using SLE multiplex families provided several chromosomal regions of susceptibility genes significantly linked to SLE.30,31 Genetic predisposition to lupus is indicated by the 11–50% monozygotic twin concordance and increased family risk.32 Several genes encoding immune components such as HLA, IRF5, ITGAM, STAT4, BLK and CTLA4 among others have been associated with predisposition to lupus.32,33 The human leucocyte antigen (HLA) class II gene has been associated with the presence of autoantibodies such as anti- Sm, anti-Ro, anti-La, anti-nRNP, and anti-dsDNA.34 Inherited complement deficiencies in HLA class III genes - particularly encoding complement components C2, C4, and C1q - are also implicated in SLE’s pathogenesis.35
Apoptosis plays a pivotal role in the pathogenesis of lupus. Apoptotic cells such as UV-light exposed keratinocytes release blebs rich in surface autoantigens, including Ro, La, and RNP.36,37 These autoantigens combined with antibodies form large aggregates of immune complexes that circulate in the bloodstream, overwhelming clearance mechanisms by phagocytic cells.38 The immune complexes are ultimately deposited in various tissues and organs, leading to acute and chronic inflammation and consequent organ damage.29
Hormonal milieu involving endogenous sex hormones at the hypothalamo–pituitary–adrenal (HPA) axis is implicated in predisposition to SLE and modulates its clinical expression.17,39 Abnormal estrogen metabolism has been demonstrated in patients with SLE of both sexes, with an increase in 16a hydroxylation of estrone, resulting in significantly raised 16a hydroxyestrone concentrations.40 Women with SLE also have low plasma androgens, including testosterone, dihydrotestosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate.41,42
Figure: Pathogenesis of SLE
| Environmental Triggers | Multiple Genes | Neuro - Endocrine System | Sex and Sex Hormones Milieu |
Immune Dysregulation
DNA
Apoptotic
Defective Clearance Mechanisms
Loss of Suppressor
Mechanisms
B Cells
APC
Excess T-Cell Help Cytokines
T Cells Autoantibodies
Defective Clearance
Immune Complexes Complement Activation
Tissue Damage
Diagnosis of Lupus
Systemic lupus erythematosus diagnosis is based on classification criteria established by the American College of Rheumatology (ACR).43 A minimum of 4 out of 11 ACR criteria should be met for accurate diagnosis. The 11 ACR criteria are the following:
Discoid rash: a rash that appears as red, raised, disk-shaped patches.
Hematologic disorder: hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia.
Immunologic disorder: anti-DNA, anti-Smith antibodies, lupus anticoagulant or positive antiphospholipid antibodies on testing.
Malar rash: a butterfly-shaped rash over the nose and cheeks; can be flat or raised.
Neurological disorder: seizures or psychosis in the absence of offending drugs or known metabolic conditions.
Nonerosive arthritis: joint pain and swelling of two or more joints.
Oral ulcers: sores, usually painless, appearing in the mouth or nasopharynx.
Photosensitivity: an unusual reaction to sun or light that causes a rash to appear.
Positive antinuclear antibody at any point in time in the absence of medications/drugs.
Renal disorder: persistent protein (>0.5 gram/day) or any cellular casts.
Serositis: pleuritis (inflammation around the lungs) or pericarditis (inflammation around the heart).
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and its modification SLEDAI-2K have been developed and validated as a reliable clinical index for measuring disease activity in SLE. It reflects persistent activity in a rash, mucous membranes, alopecia, and proteinuria and is suitable for use as a scoring system in clinical trials and studies of prognosis in SLE.44
Laboratory Tests
The most important laboratory screening measure for SLE is the blood test for antinuclear antibodies, which is highly specific, with a positive result in >95% of SLE patients.45,46 However, antinuclear antibodies are also found in conditions other than SLE; therefore, more specific tests for the detection of anti-dsDNA, anti-Sm, and antiphospholipid antibodies are required to confirm SLE diagnosis.43 The anti-dsDNA antibody test is positive in 60% of SLE patients and is considered the best biomarker for disease activity, with a specificity of almost 100%, except in elderly patients who have a lower prevalence of anti-dsDNA.47 Anti-Ro or SSA antibodies with anti-La (SSB) occur in 20% to 30% of patients. Anti-Ro antibodies are associated with subcutaneous lesions and sicca syndrome, and SSB with malar rash, subcutaneous lesions, photosensitivity, arthritis, serositis, and thrombosis. Anti-U1-snRNP occurs in 13% of patients, and anti-Sm antibodies occur in 10% of patients, especially those with oral ulcers and myositis.48 In addition to laboratory tests, renal biopsy is required for patients with renal complications.49 Recently, monitoring specific B-cell subsets as biomarkers of disease activity are also utilized.50
Clinical Manifestations
Clinical manifestations of SLE can comprise systemic symptoms and specific signs of organ-system dysfunction.10 Common presenting systemic symptoms are severe fatigue, malaise, fever, anorexia, weight loss, and lymphadenopathy.51 Patients may present with signs of systemic infection often because of their disease or side effects of treatments.11 They can also present with frequent flares resulting in inflammation-driven irreversible damage.52 Ninety percent of patients have organ-specific manifestations, including thrombocytopenia, joint inflammation such as arthralgia, arthritis, tendinitis, or stiffness in the knees, wrists, and hands.53 Joint inflammation in SLE patients is distinguished from rheumatoid arthritis by its lack of joint destruction.10,11 Myalgias and muscle weakness are common, and up to 90% of patients with SLE present with symmetrical joint pain, which is typically a migratory polyarthropathy.51 Thirty-five percent of patients will have some form of glomerulonephritis or nephrotic syndrome symptoms and signs
predicting a worse outcome.54 Lupus nephritis (LN) is a major cause of morbidity and increased mortality, with a life-long risk for severe nephritis at approximately 20%.55 The SLE patients may also present with several dermatologic findings, including discoid and malar lesions, photosensitivity, alopecia, periungual erythema, nailfold infarcts, and splinter hemorrhages.10,11 Oral mucosal ulceration occurring in 50% of all cases is also a common feature in SLE.45
Risk Factors for Lupus
Multiple environmental triggers, heritability, and co-segregation with other autoimmune diseases create a predisposition toward the development of SLE. 13,17,52 The main environmental risk factors include:
Chemical/physical factors that can cause inflammation, induce cellular apoptosis, and tissue damage.
Aromatic amines
Hydrazines
Tobacco smoke
Hair dyes
Ultraviolet light
Toxins/drugs that can modify cellular responsiveness and immunogenicity of self-antigens.
Toxins (silica, mercury)
Drugs (procainamide, hydralazine, chlorpromazine, isoniazid, phenytoin, penicillamine)
Dietary factors, select prescription medications, and supplements that affect the production of inflammatory mediators.
L-canavanine (alfalfa sprouts)
High intake of saturated fats
Echinacea
Spirulina
Vitamin E
Trimethoprim/sulfamethoxazole
Infectious agents may induce specific responses by molecular mimicry and disturb immunoregulation. These include the following:
L-Bacterial DNA / Endotoxins
RNA viruses (Retroviruses)
DNA viruses (Cytomegalovirus and Epstein-Barr virus)
Hormones and environmental estrogen.
Hormonal replacement therapy
Oral contraceptive pills
Prenatal exposure to estrogens
Psychological Stress.
Trauma
Post-traumatic stress disorder
Vaccination.
Medicines for the treatment of lupus affecting immunization.
Inability of the immune system to produce protective antibodies.
Special Populations
Pregnancy
Since SLE onset is often in young adulthood, pregnancy is common and is usually successful. However, pregnancy in SLE is considered a high-risk factor in which maternal and fetal mortalities are significantly increased.56–59 Pregnant women with active SLE have more than twice the cumulative rate of adverse pregnancy outcomes (APOs) than healthy pregnant women.60–63 These APOs include preeclampsia, preterm delivery, pregnancy loss, intrauterine growth restriction (IUGR), and other problems such as thrombosis and infection.64,65 The predictors of APO involve active maternal disease, nephritis, proteinuria, hypertension, thrombocytopenia, and the presence of antiphospholipid antibodies (aPLs), particularly lupus anticoagulant.66–68 Pregnant women with SLE, especially the ones with associated antiphospholipid syndrome (APS), have repeated miscarriages and fetal loss.69
Risk of SLE flare is also higher during pregnancy with variable flare rates between 25% to 65% depending on patient populations.70 Moreover, pregnancy may carry a very high maternal risk in a subset of patients with SLE and should be avoided in women with the following conditions:58
Severe pulmonary hypertension (systolic pulmonary artery pressure
>50 mm Hg)
Severe restrictive lung disease (forced vital capacity <1 L)
Advanced renal insufficiency (creatinine level >2.8 mg/dL)
Advanced heart failure
Previous severe preeclampsia or HELLP (hemolysis, elevated liver enzyme levels, low platelet count) despite therapy
Stroke within the previous 6 months
Severe disease flare within last 6 months
Despite the adverse factors women with SLE can nevertheless have successful pregnancies provided there is an optimal timing of conception and close monitoring to risk stratify and plan management strategy for each pregnancy.
Pediatric Patients
Pediatric SLE most frequently occurs between the ages of 12 and 18 years and represents ∼15–20% of all SLE patients. While presentation, clinical symptoms, and immunological findings are like those of adult SLE in many respects, pediatric SLE is different.71,72 Children typically have a more severe disease at the onset with more frequent discoid rash, higher rates of organ involvement, and a more aggressive clinical course.73,74 However, damage to certain organs, like the kidneys, can appear more often in childhood lupus.16
Although pediatric SLE patients have a higher incidence of major organ involvement, the mortality rate is low.75 Manifestations frequently begin with renal, neurological, hematological, and atypical (abdominal) complications.76 The incidence of LN is more common in the childhood-onset form of SLE.77,78 Ethnicity also influences SLE manifestations, with Hispanic and African
American children having higher incidence, greater prevalence, and severity of renal and CNS involvement.78,79 Serologically, anti-DNA, anti-Sm, anti-RNP antibodies, and low C3 are also found more frequently in the younger SLE patients.80
Treatments for Managing Lupus
Treatment of SLE is highly individualized and depends on symptom manifestations, organ involvement, disease severity, and the patient’s response.2,44 Childhood lupus usually requires more aggressive treatments than adult lupus; however, clinicians must guard against the risk posed by some long-term medications (e.g., prednisone).16
Nonpharmacological Treatments
Patient education and psychosocial support are important aspects of SLE nonpharmacological management and are recommended by both EULAR and ACR guidelines.2,44 All patients with SLE are counseled on lifestyle modifications and guided to:
Avoid direct exposure to sunlight and use sunscreen blockers of both UVA and UVB rays.
Cease smoking.
Maintain proper nutrition and weight control.
Maintain adequate intake of calcium and vitamin D.
Ensure adequate exercise.
Alleviate depression and anxiety.
Screen for bone loss.
Pharmacological Treatments
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Drugs such as celecoxib, piroxicam, and ketorolac are commonly used to relieve arthralgia, inflammation, serositis, and fever in SLE. The
maximum celecoxib dose is 200 mg twice daily. The maximum dose of piroxicam is 20 mg daily in adults.81 These can be used with or without low doses of steroids or antimalarial agents.2,82 When taking NSAIDs, it is important to use the lowest dose that is effective and take it for the shortest time. Adverse events are common, especially gastrointestinal bleeding, including upper and lower gastrointestinal tract complications.83 NSAIDs may worsen kidney function or contribute to fluid retention, so monitoring should occur.84 Refer to the full prescribing information of each prescribed agent for comprehensive safety and efficacy.
Low-dose aspirin is also prescribed in some individuals suffering from lupus.85 It has pain-reducing, anti-inflammatory, and anticoagulant properties.
Antimalarials
Drugs such as hydroxychloroquine and chloroquine are non- immunosuppressive agents that are used to reduce flares, prevent organ damage, and is particularly useful for arthralgias and cutaneous SLE.86,87 Hydroxychloroquine, is frequently used as a first-line treatment to prevent the occurrence of mild SLE manifestations.88 It has been shown to maintain remission, protect against vascular and thrombotic events, and improve lipid levels.89,90 It can also be used during pregnancy.2 Hydroxychloroquine is dosed as 200 mg once daily or 400 mg once daily (or in two divided doses) in adults.91 Chloroquine is not FDA-approved for lupus. The common side effects are gastrointestinal upset, dermatologic reactions, headache, and light-headedness. Retinal toxicity and macular damage can occur over time due to drug accumulation in the ocular tissue.45,51
Glucocorticoids
Drugs such as prednisone and prednisolone affect all components of the immune system and are used at low doses for mild SLE or treatment of
cutaneous and musculoskeletal symptoms not responding to other therapies.86 Higher doses given systemically are used for patients with significant organ involvement or refractory symptoms.82 Generally, less than 7.5 mg/day of prednisone is considered a low dose, and more than 30 mg/day is considered a high dose.92 Long-term complications with glucocorticoids include myopathy, osteoporosis, hypertension, diabetes, atherosclerotic vascular disease, and infections.45
Cytotoxic/immunosuppressive agents
Cyclophosphamide is a highly toxic alkylating agent that depletes T and B cells and suppresses antibody production.93 It is available as 25 mg and 50 mg tablets and as an injection.94 In the past, it was widely used for LN and severe lupus in the central nervous system.95,96 However, currently, it has been replaced by less toxic immunosuppressive medications such as mycophenolate mofetil, calcineurin inhibitors, and azathioprine. Cyclophosphamide is associated with premature ovarian failure, hemorrhagic cystitis, increased risk of bladder and other malignancies, along with leukopenia an increased risk of infections.97
Mycophenolate mofetil (MMF) has similar efficacy as cyclophosphamide but with a better safety profile. It is available as 250 mg capsules and 500 mg tablets, 35 mg powder for oral suspension (200 mg/ml when reconstituted), and injection.98 It preferentially depletes guanoside nucleotides in T and B cells, inhibiting proliferation and suppressing lymphocyte and monocyte recruitment to the inflamed tissue.99 Mycophenolate mofetil is effective for the induction and maintenance of LN nephritis and is superior to azathioprine in preventing nephritis relapses.13,100
Azathioprine (AZA) is a purine analog that inhibits DNA and RNA synthesis, preventing lymphocyte proliferation in the immune system. It is used as a steroid-sparing agent in moderate to severe lupus and in the maintenance phase of LN.82,88 Azathioprine is a safe immunosuppressant to control renal and extrarenal disease during pregnancy since its prodrug 6-MMP is associated with hepatotoxicity and
myelotoxicity is not generated in the fetus.58,101 Azathioprine can be dosed as 2 mg/kg/day.102
Methotrexate (MTX) is an antifolate metabolite that interferes with DNA synthesis, repair, and replication.103 Methotrexate is commonly used as an anti-inflammatory agent to treat rheumatoid arthritis. It has been dosed as 15-20 mg/week (preferably subcutaneously).104 In lupus, the drug reduces disease activity, acts as a corticosteroid-sparing agent, has efficacy for joint and skin disease, and lowers anti-dsDNA and complement levels.105 Side effects include nausea, mouth sores, blood problems, liver damage, and moderate hair loss. Prolonged treatment with methotrexate may also lead to folic acid deficiency.106
Calcineurin inhibitors such as tacrolimus target T cells by blocking the inhibition of calcineurin, which results in a reduction of inflammatory cytokines IL-1b, IFN-γ, IL-6, and IL-10. B cell activation is also impaired along with class switching and immunoglobulin production.107 Combination of tacrolimus and mycophenolate is an effective therapy for refractory LN, maintenance LN, and pure membranous LN with a significant antiproteinuric effect.97,108,109 Voclosporin is a newly approved calcineurin inhibitor that has greater pharmacological potency in active LN with a higher complete remission rate than mycophenolate.110 Before initiating it, an accurate baseline estimated glomerular filtration rate (eGFR) should be established, and blood pressure (BP) checked. Voclosporin must be swallowed whole on an empty stomach. It is administered as close to a 12-hour schedule as possible, and with at least 8 hours between doses. Grapefruit or grapefruit juice should be avoided. It is available as a 7.9 mg dose. The recommended starting dose is 23.7 mg orally, twice a day. It is used in combination with mycophenolate mofetil (MMF) and corticosteroids. Reduced dosing is recommended for hepatic or renal insufficiency.111
Biologics and small molecules
Belimumab is a human monoclonal antibody with a unique mechanism of action that blocks the biologic activity of B-lymphocyte stimulator (BLyS/BAFF). This decreases the antibody levels in the body, leading to a reduction of the autoimmune activity of SLE.112 Belimumab is the first FDA-approved drug for active lupus and LN in adults and children (age
5 and above) and for patients with autoantibody-positive SLE receiving standard therapy.113 In clinical trials, it demonstrated a steroid-sparing effect, decreased rate of flares, and good safety profile.114 The intravenous dosage for adult and pediatric patients with SLE or LN is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter. It is reconstituted, diluted, and administered as an intravenous infusion over a period of 1 hour. The subcutaneous (subq) dosage for adults with SLE is 200 mg once weekly. The subq dosage for adults with LN is 400 mg (two 200-mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter.
Rituximab is a humanized chimeric mouse/human monoclonal antibody that targets B-cell-specific antigen CD20. It leads to peripheral B-cell depletion of autoreactive B-cells in the circulation of patients with SLE. Although not approved by the FDA, it is often used off-label for severe refractory SLE.115 Several observational studies showed benefits in renal and non-renal lupus.116,117
Anifrolumab is a monoclonal antibody that inhibits excess interferon activation by blocking type I IFN-α/β/ω receptor (IFNAR). The effect is greater in SLE patients with high interferon signature at baseline.118 Treatment is associated with decreased anti-dsDNA titers and higher C3 levels. However, common adverse events are present such as upper respiratory and urinary infections as well as shingles.119 Anifrolumab has been recently approved by FDA for the treatment of patients with moderate-to-severe SLE.120 The recommended dosage is 300 mg as an intravenous infusion over a 30-minute period every 4 weeks. Patients are informed that they should not receive live or live-attenuated vaccines while receiving anifrolumab.121
Ustekinumab is a fully human monoclonal antibody that inhibits p40 subunit of Interleukin (IL)-12 and IL-23. Results of Phase II open-label study in patients with active SLE demonstrated clinical benefit in global and organ-specific measures with no adverse safety findings.122 Subgroup analysis showed significant improvement in skin and joint scores, improved C3, and reduced anti-dsDNA levels.122 However, more recent data from Phase III randomized, placebo-controlled study did not demonstrate superiority over placebo in adults with active SLE.123
Baricitinib is an orally administered, small-molecule, Janus-associated kinase (JAK) inhibitor. JAK1 and JAK2 mediate signaling for type 1 interferons, IFN-γ, IL-6, IL-12, and IL-23, among several other cytokines. Baricitinib is currently approved for the treatment of rheumatoid arthritis. In SLE results of a 24-week Phase II in patients receiving baricitinib at 4 mg showed significant improvement in SLE activity. Recent data from a 52-week Phase III clinical trial, however, indicates that despite meeting the primary endpoints, treatment with baricitinib at 4 mg did not meet secondary endpoints and was associated with serious adverse events.124
Atacicept is a TACI-Ig fusion protein that inhibits B cells by dual inhibition of APRIL and BAFF, the two key factors produced by a variety of cells, including monocytes, dendritic cells, and T cells that help to regulate B cell maturation. A Phase II/III randomized clinical trial in patients with active LN on immunosuppressive therapy failed to evaluate the efficacy and safety of atacicept due to an unexpected decline in serum IgG and serious infections.125
Management of Flares
Relapses or flares are frequently observed in 27–66% of patients with SLE. Management of flares involves mitigation of risk factors that may trigger flare-ups such as environmental, hormonal, or medication-related toxic effects. Effective therapy targeting low-disease activity or remission has the potential to decrease the frequency and severity of lupus flares.52 Typically, patients stable on treatment experiencing lupus flare, are temporarily given high-dose corticosteroids to reduce inflammation. Nephritic flares are common in patients with proliferative LN, and these are usually controlled with pulse immunosuppressive therapy.126 Mycophenolate mofetil and azathioprine treatment are effective for renal, proteinuric, and nephritic flares.127 Data from meta-analysis studies indicates that mycophenolate mofetil is superior to azathioprine in preventing LN flares during maintenance.128 Belimumab decreases severe SLE flares while reducing prednisone dependence.114 Reduced risk of cumulative damage and flares are also routinely mitigated with hydroxychloroquine.129 Tacrolimus is relatively safe and effective in treating lupus flares during pregnancy.130 In addition, intramuscular
triamcinolone, or a brief 1-week methylprednisolone is effective for the management of most mild to moderate flares.13
Management of Depression
The neuropsychological symptoms, including anxiety, psychiatric and mood disorders associated with depression, are frequent in 45–65% of patients with SLE.131 Lupus patients also have a higher risk of suicidal tendencies than the general population.132 Such symptoms are attributed to either the psychosocial impact of the disease or to the presence of lesions in the central nervous system.132 Management of depression in SLE depends on whether it is diagnosed as a neurological disease (e.g., inflammation of the brain, stroke, seizure, presence of autoantibodies, elevated cytokines) or as a psychological disorder where signs of neurological disease are absent. Behavioral interventions such as targeted referrals to patient educators, mental health professionals, and support organizations in adjunct to antidepressant treatment are used to manage the neuropsychological symptoms.133 Cognitive behavioral stress management techniques have resulted in short-term improvement in pain, psychological function, and perceived physical function in SLE.134
The neurological basis of depression in SLE is attributed to multiple factors involving alteration of neurotransmitters bioavailability, overstimulation of neural circuits, cytokines, modification of neuroplasticity, and neurogenesis; all these can cause mood swings and depression.135 SLE patients with neurological cases are treated with glucocorticoids, immunosuppressants, and antidepressants.136 Combination of celecoxib (anti- inflammatory) and fluoxetine (antidepressant) has been reported to have a greater effect than fluoxetine alone.137 Electroconvulsive therapy (ECT) can be used in severe cases of patients who do not respond to the maximum therapy.138 Overall, most SLE patients with depression recover within a year with the help of social support along with medical care.132
Counseling Patients with Lupus
Social workers and clinical practitioners play a central role in helping patients with SLE to cope with the diagnosis and manifestations of this complex and highly individualized disease. To develop effective counseling and intervention strategies, they must learn how lupus affects the physical, psychological, and social functioning of patients and their families. The most commonly reported problems in lupus include depressed feelings, reduced physical activity, stress, and changes in body image. These fall in the areas of
(i) emotional aspects, (ii) lack of information, (iii) lifestyle restrictions, and
(iv) lack of information regarding exercise and diet.139 These four factors are identified and used as specific educational themes in developing education programs for SLE patients. Along with medical management, practitioners working with SLE patients should consider approaches such as patient- centered narrative and strengths-based perspective.140 The counselor’s role is to assist individuals in learning positive ways of adapting to the realities of living with an ongoing disease with chronic symptoms. It is important for the social worker and the health care practitioner to help patients with lupus accept, adjust, and develop a plan for living for the future.
Pharmacy team members can support an interdisciplinary approach to care by creating a rapport with patients, fully explaining all medications, and emphasizing adherence. Patients should be encouraged to minimize direct exposure to the sun, use SPF 30 and higher sunscreen, and be aware of medications that increase sensitivity to the sun. Counseling on photosensitivity is also appropriate for patients with lupus who have skin of color, including African American, Hispanic, Asian, and Native American populations.141 Patients with lupus can be encouraged to seek interpersonal and social support. Patient counseling may include inquiring whether any daily activities contribute to fatigue and encouraging individuals to get enough sleep. Patients with nutrition-related lupus complications should be referred to a dietician for counseling.
Gap Analysis of Current Versus Best Practices for Management of SLE
The diverse nature of SLE poses great challenges to research and drug development efforts. Treatment of SLE is highly individualized and depends on a specific patient’s profile that considers diagnosis, disease activity, and prediction of disease course and flares. Autoantibodies and immune complex formation are the immunological hallmarks of lupus. Due to this, B cells have been targeted in SLE for many years with immunosuppressants such as cyclophosphamide and mycophenolate. Recent improvements in patient care and the use of immunosuppressives with corticosteroids have changed the course of SLE. Survival has improved dramatically over the past 5 decades from a 5-year survival of 50% to a 15-year survival of 85% with current medical regimens.142 Despite such advances, further improvement in survival has mostly stalled, and the rate of progression to renal failure has not improved.143 LN is the most common severe organ-threatening manifestation of SLE that causes high morbidity and mortality however, only 20-30% of LN patients achieve complete remission with the current treatment paradigm.144,145 During the past decade, novel combinations of immunosuppressive drugs and biologicals have been added to the therapeutic armamentarium, including anifrolumab for moderate to severe SLE and belimumab and voclosporin for active LN.110,113,120 Antimalarials are currently the basic treatment for every patient with SLE, whereas glucocorticoids are only used when acutely indicated.104 Adjunct treatment is almost as important as immunosuppression and is a comedication, which is determined by the comorbidity type (e.g., infection, arteriosclerosis, hypertension, dyslipidemia, diabetes, osteoporosis, avascular necrosis, and malignancy, among others).104
The emphasis in the management of lupus has shifted from individual drugs to a strategy that aims at early, sustained remission tailored to disease manifestations and severity with the lowest possible toxicity. Infections and accelerated atherosclerosis (attributed to both traditional and non-traditional risk factors) and thrombosis-related clinical events (including arterial, venous, and pregnancy loss) still represent a major challenge in the management of the disease. Treatment goals for SLE currently include long-term patient survival, prevention of organ damage, and optimization of health-related quality of life.
Future Approaches to Managing Lupus
Future perspectives for the management of SLE/lupus will be designed as individualized treatments depending on the presenting symptoms and disease progression of each patient. The goal is to develop a personalized plan geared to lessen the impact of the disease on a patient's life. Biologic compounds that target specific immunologic mechanisms offer a new paradigm in the treatment of SLE. At best, these could reverse the course of the disease and, at the very least, could provide new alternatives to reduce symptoms and limit tissue damage without contributing to overall morbidity and mortality. Strategies using genomics and proteomics will aid in identifying new biomarkers that can be used for early disease detection and treatment.
Summary
Systemic lupus erythematosus is a challenging and disabling autoimmune disease affecting many organs. Multiple biological mechanisms contribute to the development and progression of the disease. Clinical manifestations can be both systemic and organ-specific depending on the type of disease. Systemic lupus erythematosus is associated with frequent flares and relapses that are often triggered by risk factors. Special populations such as pregnant women and pediatric patients with SLE are particularly at risk of developing adverse effects. Advances in research and drug development have led to target-specific effective and less toxic therapeutics. The goal of SLE treatment is to achieve long-term remission, reduce morbidity/mortality and improve quality of life. This could be attained through broad efforts of basic, translational, and clinical scientists, clinicians, patient counselors, patients, and their families, and everyone engaged in the lupus community.
Course Test
What is a laboratory test utilized for the diagnosis of SLE?
blood test for antinuclear antibodies
radiographic X-ray, CT, and MRI
ophthalmic retina biopsy
PCR COVID test
Which of the following is not a drug that has been prescribed for the treatment of SLE?
Cyclophosphamide
Belimumab
Hydrazine
Hydroxychloroquine
Which of the following SLE patient populations is more at risk of developing a new diagnosis of SLE and adverse outcomes?
Pregnant women
80-year-old African American
3-year-old Hispanic/Latino
90-year-old Asian
Which of the following statements is correct?
A minimum of 6 out of 11 ACR criteria ought to be met for a diagnosis of SLE.
Positive antinuclear antibody is not an ACR criteria for diagnosis of SLE.
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and SLEDAI-2K are the criteria.
Lupus is a chronic, progressive autoimmune disorder in which the immune system attacks its own healthy tissues.
Which of the following biologics is used to decrease severe SLE flares with an intravenous or subcutaneous dosing option?
Anifrolumab
Ustekinumab
Belimumab
Rituximab
Which of the following statements is correct?
Management of depression in SLE depends on whether it is diagnosed as a neurological disease or behavioral disorder.
The neuropsychological symptoms of SLE include anxiety, depression, psychiatric and mood disorders.
SLE patients with neurological cases are treated with glucocorticoids, immunosuppressants, and antidepressants.
All of the above
The most common side effect associated with the use of NSAIDs in SLE is:
Vascular thrombosis
Gastrointestinal bleeding
Immune tolerance
Renal toxicity
Which 2 of the following novel drugs has been recently approved for SLE by FDA?
Cyclosporine and erythromycin
Voclosporin and belimumab
Anifrolumab and methotrexate
Timolol and aspirin
Future approaches for the development of new SLE drugs could include
individualized treatment depending on the presenting symptoms and disease progression of each patient.
only achieve short-term remission with new autoantibodies.
new anti-inflammatory cytokines because all lupus cases appear suddenly.
new aromatic amines because only amines prevent all photosensitivity.
Which of the following risk factors creates a predisposition to SLE?
Environmental triggers
Heritability
Autoimmune diseases
All of the above
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