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Systemic lupus erythematosus: modern strategies for management – a moving target

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Rapid advances in understanding the immunopathogenesis of systemic lupus erythematosus (SLE) have yielded an unprecedented era of discovery of new targets with therapeutic potential. Recent clinical trials have also shed light on the optimal utility of several traditional therapies used in our SLE armamentarium.

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

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