1Systemic lupus erythematosus: modern strategies for management – a moving target
Introduction
Over the last decade, there have been significant advances in our understanding of systemic lupus erythematosus (SLE). However, despite this scientific progress, no new medications have been approved by the US Food and Drug Administration (FDA) since 1966. Our modest arsenal of approved drugs includes aspirin, corticosteroids, and hydroxychloroquine. The challenges of developing new drug treatments for SLE are multi-faceted. Difficulties include an incomplete understanding of the complex interplay of pathogenic factors, the inherent heterogeneity of clinical disease, absence of biomarkers that are specific and sensitive for disease response in most patients, and the adverse effects of current and newer therapies. In addition, the FDA has only recently published guidance for the pharmaceutical industry in the form of a roadmap detailing clinical metrics and measures of response that may lead to drug approval.1 This chapter describes currently used therapies that are deemed relatively safe and effective, and explores biologics and future investigational therapies in the management of SLE.
Our targets for SLE therapeutics are largely based on our knowledge of the pathogenic mechanisms leading to clinical disease (Figure 1). In broadly simplified terms, genetic predisposition in combination with a variety of environmental factors – such as female gender, ultraviolet (UV) B light, and infection with Epstein–Barr virus – results in an abnormal immune response that breaks the body's tolerance to self antigens. Hence the immune system recognizes its own self antigens as targets against which to mount immune responses, which, in some individuals, lead eventually to autoimmune disease. The key players involved in this abnormal immune response include antigen-presenting cells (APCs) such as macrophages and dendritic cells, T lymphocytes, B lymphocytes, and plasma cells. Immune stimulation via culprit self antigens – such as histones in double-stranded DNA (dsDNA), RNA/protein in Sm, Ro, La, and phospholipids – occurs, leading to direct and/or T-cell-stimulated B cells, which mature to plasma cells that produce autoantibodies. These autoantibodies bind directly to tissues or form immune complexes, which circulate, deposit in tissue, fix complement, and cause inflammation, cell impairment or destruction, and subsequent structural organ damage.
Section snippets
Conservative therapies for mild disease (nonlife-threatening)
Mild SLE symptoms include constitutional symptoms of fatigue and fever, joint pain and/or swelling, headache, and/or serositis. Patients with mild SLE activity, without major organ-threatening disease, can be prescribed salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, topical therapies, antimalarials, and dehydroepiandrosterone (DHEA) for symptom relief.
The short-term efficacy of aspirin over NSAIDs in SLE was shown in 1980, when the National Institutes of Health (NIH)
Glucocorticoids
The use of systemic glucocorticoids (GCs) improves severe, organ-specific manifestations of SLE and improves survival in patients with proliferative glomerulonephritis.30, 31 Dosages vary based on clinical severity of SLE symptoms, but can be classified as: (1) pulse intravenous (IV) therapy: methylprednisolone IV 1 g × 3 days, followed by high-dose 0.6–1 mg/kg daily oral prednisone or equivalent; (2) very-high-dose oral GC at > 1–2 mg/kg/day prednisone or equivalent; (3) high-dose GC at 0.6–1
Therapies for patients with lupus nephritis
Treatments for proliferative glomerulonephritis (PGN) have been among the best-studied SLE organ-specific clinical regimens with evidence-based outcomes. The initial landmark trials performed at the NIH showed the superiority of high-dose IV cyclophosphamide (CYC) in dosages of 0.5–1 g/m2 body surface area (BSA) every month for 6 months, followed by quarterly dosages (plus GCs), over GC therapy alone.33, 34, 35, 36 However, because of the variability of progression of proliferative nephritis in
Therapies for patients with non-nephritis SLE
Standard immunosuppressive therapies for non-nephritic manifestations of SLE have included the above-mentioned regimens, as well as methotrexate (MTX), calcineurin inhibitors such as cyclosporine, intravenous immune globulin (IVIG), and plasmapheresis. Of note, there are fewer randomized controlled trials studying therapies for SLE in patients without nephritis. Hence, in the absence of other trials, the use of CYC and steroids in severe organ involvement is generally based on nephritis studies.
Biologics and future therapies
Targeting individual components of the immune system repertoire (see Figure 1) has led to an expansion in treatment alternatives for autoimmune disease. Many prospective, controlled, randomized clinical trials using biologics with specific targets are currently in progress in patients with SLE, many studying patients both with and without nephritis.
Summary
In the past decade, advances in the area of lupus have led to a significant expansion in our armamentarium of therapeutics, although none is yet approved by the FDA for use in SLE. The use of mycophenolate mofetil has been a substantial advance. Recent clinical trials have shed light on optimizing usages and alternatives of more traditional therapies, such as antimalarials, cyclophosphamide, azathioprine, and mycophenolate mofetil. In addition, targeting components of the immune system has
References (109)
- et al.
Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis
American Journal of Medicine
(1994 Mar) - et al.
Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids
American Journal of Medicine
(1990 Sep) - et al.
On the inhibitory effect of chloroquine on blood platelet aggregation
Thrombosis Research
(1994 Jun 1) Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy
American Journal of Medicine
(1983 Jul 18)- et al.
Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis
Lancet
(1992 Sep 26) - et al.
Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network
Kidney International
(1997 Apr) - et al.
Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus
American Journal of Medicine
(1995 Jan) - et al.
Pimecrolimus 1% cream for cutaneous lupus erythematosus
Journal of the American Academy of Dermatology
(2004 Sep) - et al.
Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE
Clinical Immunology
(2007 Jan) Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus erythematosus
Rheumatic Diseases Clinics of North Americas
(2006 Feb)
Comparative effects of aspirin and ibuprofen in the management of systemic lupus erythematosus
Arthritis & Rheumatism
NSAID usage patterns by rheumatologists in the treatment of SLE
The Journal of Rheumatology
Sulindac-induced aseptic meningitis
Archives of Internal Medicine
Tolmetin-induced aseptic meningitis
Journal of American Medical Association
Naproxen-induced recurrent aseptic meningitis
DICP
Reversible renal failure and nephrotic syndrome associated with nonsteroidal anti-inflammatory drugs
The New England Journal of Medicine
Sensitization to ibuprofen in systemic lupus erythematosus
Journal of American Medical Association
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group
The New England Journal of Medicine
Risk of cardiovascular events associated with selective COX-2 inhibitors
Journal of American Medical Association
Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual
Arthritis & Rheumatism
The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus
The Journal of Rheumatology
Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice
Circulation
Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus
Annals of the Rheumatic Diseases
Dosage of hydroxychloroquine should be based on ideal body weight: comment on the letter by Alarcon
Arthritis & Rheumatism
The association of the two antimalarials chloroquine and quinacrine for treatment-resistant chronic and subacute cutaneous lupus erythematosus
Dermatology
Antimalarial Therapies
Low plasma androgens in women with systemic lupus erythematosus
Arthritis & Rheumatism
Dehydroepiandrosterone sulfate is positively correlated with soluble interleukin 2 receptor and soluble intercellular adhesion molecule in systemic lupus erythematosus
The Journal of Rheumatology
Hormones and lupus: defective dehydroepiandrosterone activity induces impaired interleukin-2 activity of T lymphocytes in patients with systemic lupus erythematosus
Annales de médecine interne
Disassociation of sex hormone levels and cytokine production in SLE patients
Lupus
Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial
Arthritis & Rheumatism
Dehydroepiandrosterone in systemic lupus erythematosus. Results of a double-blind, placebo-controlled, randomized clinical trial
Arthritis & Rheumatism
Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial
Arthritis & Rheumatism
A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus
Lupus
Evaluation of treatment in lupus nephritis: effects of prednisone
American Journal of kidney diseases
The natural history of the renal manifestations of systemic lupus erythematosus
The Journal of laboratory and clinical medicine
Systemic Glucocorticoid Therapy in Systemic Lupus Erythematosus. Dubois' Lupus Erythematosus
Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs
The New England Journal of Medicine
Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial
Annals of Internal Medicine
Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis
Annals of Internal Medicine
Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide
Arthritis & Rheumatism
Clinical features of systemic lupus erythematosus: differences related to race and age of onset
Arthritis & Rheumatism
Outcome of end-stage renal disease in patients with rare causes of renal failure. III. Systemic/vascular disorders
The Quarterly Journal of medicine
Clinical manifestations of systemic lupus erythematosus. Identification of racial and socioeconomic influences
Archives of Internal Medicine
Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial
Arthritis & Rheumatism
Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group
The New England Journal of Medicine
Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis
Chinese Medical Journal
Sequential therapies for proliferative lupus nephritis
The New England Journal of Medicine
Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis
The New England Journal of Medicine
Cited by (12)
Stories of drug repurposing for pancreatic cancer treatment-Past, present, and future
2020, Drug Repurposing in Cancer Therapy: Approaches and ApplicationsTreatment of autoimmune disease: Established therapies
2019, The Autoimmune DiseasesTreatment of Autoimmune Disease: Established Therapies
2013, The Autoimmune Diseases: Fifth EditionSER Consensus statement on the use of biologic therapy for systemic lupus erythematosus
2013, Reumatologia Clinica