Overview of the management and prognosis of systemic lupus erythematosus in adults

INTRODUCTION — Systemic lupus erythematosus (SLE) is a chronic, occasionally life-threatening, multisystem immune-mediated disorder. Patients may present with a wide array of symptoms, signs, and laboratory findings and have a variable prognosis that depends upon the disease severity and type of organ involvement. Establishing the diagnosis of SLE may be challenging, and the approach to the diagnosis and differential diagnosis of SLE is presented separately. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)

Due to the variable disease course, effective management of SLE requires regular clinical and laboratory monitoring to assess disease activity, to guide therapy to alleviate symptoms and reduce progressive organ damage, to prevent and treat relapses, to assess side effects related to drug therapy, to encourage adherence with medications, and to coordinate care with the patient's other providers.

This topic will review the general issues related to the management of patients with SLE. The treatment of specific organ involvement is discussed in separate topic reviews:

●(See "Overview of cutaneous lupus erythematosus" and "Initial management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus" and "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy".)

●(See "Treatment of Raynaud phenomenon: Initial management" and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)

●(See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus".)

●(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis" and "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy" and "Lupus nephritis: Therapy of lupus membranous nephropathy" and "Kidney transplantation in adults: Issues related to lupus nephritis".)

●(See "Gastrointestinal manifestations of systemic lupus erythematosus".)

●(See "Pulmonary manifestations of systemic lupus erythematosus in adults".)

●(See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Coronary artery disease in systemic lupus erythematosus".)

●(See "Hematologic manifestations of systemic lupus erythematosus".)

●(See "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system" and "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus".)

GENERAL PRINCIPLES

Goals and overview of therapy — The goals of therapy for patients with systemic lupus erythematosus (SLE) are to achieve remission or low disease activity, prevent organ damage, minimize drug toxicity, and improve quality of life [1,2].

Treatment of SLE is individualized based upon patient preferences [3], clinical manifestations, disease activity and severity, and comorbidities. Patients require monitoring at regular intervals by a rheumatologist or other provider to optimize both nonpharmacologic and pharmacologic therapies and achieve treatment goals. Patients often have multiorgan system involvement and may require multidisciplinary care, including involvement of nephrology, dermatology, and hematology.

Our management strategy for SLE is generally consistent with guidelines developed by professional organizations, including the European Alliance of Associations for Rheumatology (EULAR; formerly European League Against Rheumatism) [2,4], the British Society for Rheumatology [5,6], and others [7]. Specific guidelines for the management of lupus nephritis are discussed separately in the relevant topics.

Definitions

●Flare – The clinical course of SLE is variable and may be characterized by unpredictable disease flares and remissions. There is no consensus on what constitutes a disease flare, but most clinicians agree that a flare refers to a measurable increase in disease activity that is clinically meaningful enough to result in a change in therapy [8-10]. Flares are generally categorized by severity, with moderate or severe flares being the most clinically significant. A challenge in clinical practice is to stratify patients at risk for disease flares. We typically use various laboratory tests to help assess disease activity in the context of the clinical presentation and organ domain involvement to evaluate for a disease flare. (See 'Laboratory evaluation' below.)

●Remission – There has been a lack of consensus on a definition of remission, despite it being a goal of therapy. Complete remission has been described as the absence of physical and laboratory abnormalities associated with SLE without the use glucocorticoids or immunosuppressive therapy, but is rarely achieved [11-14].

The Definitions of Remission in SLE (DORIS) Task Force proposed a definition of remission that is based on the absence of clinical disease activity as measured by the clinical Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) = 0 and physician global assessment (PGA) <0.5. The patient may be on antimalarials, low-dose glucocorticoids (eg, prednisone ≤5mg/day), and/or maintenance doses of immunosuppressive therapies [15].

●Low disease activity – Various concepts of low disease activity states have been proposed, including the Lupus Low Disease Activity State (LLDAS) [16-18]. The LLDAS accepts a SLEDAI-2K ≤4 with no activity from major organ systems, no new clinical activity compared with the previous assessment, a PGA of ≤1, prednisone dose ≤7.5 mg/day and maintenance doses of antimalarials and immunosuppressive therapies [18]. Active serology (anti-double-stranded deoxyribonucleic acid [dsDNA] and complement C3/C4) counts toward disease activity in the LLDAS definition. The various definitions of low disease activity states are associated with comparable rates of remission in terms of halting damage accrual and prevention of flares [19-23].

Definitions for complete remission or response for lupus nephritis are discussed in detail separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Definitions of response'.)

ASSESSMENT OF DISEASE ACTIVITY — Given the heterogeneity of disease presentation and clinical course among patients with systemic lupus erythematosus (SLE), an assessment of disease activity should be performed at each clinic visit. Features attributable to active SLE must be distinguished from chronic damage, drug toxicities, and other conditions such as infection or fibromyalgia (or chronic centralized pain). As an example, marked proteinuria and a reduced glomerular filtration rate may result from either active inflammation or scarred glomeruli. Differentiating between these two possibilities has significant therapeutic implications, since immunosuppressive therapy should not be escalated in the latter setting. Similarly, joint pain may be related to active synovitis for which glucocorticoids may be indicated, or it may be due to avascular necrosis which is a side effect of treatment with glucocorticoids. Diffuse joint pain must also be distinguished from pain related to fibromyalgia (or central sensitization).

History and physical examination — All organ systems must be reviewed since almost any organ can be involved in SLE. If specific symptoms are present, patients should also be asked about any potential triggers such as sun exposure, infection, or discontinuation of therapy.

The physical examination should include evaluation of the skin (including scalp and mucous membranes) and lymph nodes, as well as respiratory, cardiovascular, abdominal, musculoskeletal, and neurologic systems. A more detailed discussion of all of the clinical manifestations associated with SLE is presented separately. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

Laboratory evaluation — Laboratory tests are also used to help assess disease activity and monitor organ-specific complications (eg, lupus nephritis) [24]. Since there is no single marker of disease activity, clinicians must interpret the laboratory results in the appropriate clinical context. We obtain laboratory testing to assess disease activity at least every six months and more frequently in patients with active disease. (See 'Monitoring response to therapy' below.)

●Laboratory tests – We typically check the following laboratory tests when monitoring disease activity in all patients with SLE:

•Complete blood count (CBC) with differential – Leukopenia is common and may reflect active disease. Anemia and thrombocytopenia may also be observed with active disease. Cytopenias may also result from drug toxicities. (See "Hematologic manifestations of systemic lupus erythematosus".)

•Acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) – Increases in acute phase reactants are commonly observed in patients with SLE, and therefore may not be as reliable for detecting disease activity as is the case with other inflammatory diseases [25-28]. Nonetheless, an elevated ESR can be associated with increased disease activity and accrued damage [28,29]. Similarly, elevations in CRP can also be associated with disease activity. There are conflicting data on the diagnostic value of a markedly elevated CRP in distinguishing active SLE from infection; however, an elevated CRP should raise the suspicion for infection in a patient with SLE [30,31].

•Urinalysis with urinary sediment – Proteinuria or cellular casts and hematuria may be due to SLE involving the kidney. (See "Lupus nephritis: Diagnosis and classification".)

•Spot urine protein-to-creatinine ratio – Quantification of proteinuria helps assess the severity of glomerular disease [32].

•Serum creatinine and estimated glomerular filtration rate (eGFR) – Elevations in serum creatinine may reflect lupus nephritis.

•Anti-double-stranded DNA (dsDNA) – Titers of anti-dsDNA antibodies often fluctuate with disease activity, particularly in patients with active glomerulonephritis. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)

•Complement levels (C3 and C4) – Low C3 and C4 and/or elevated C3 and C4 activation products often indicate active disease, particularly lupus nephritis. (See "Lupus nephritis: Diagnosis and classification".)

With the exception of anti-dsDNA antibodies, we do not repeatedly check antinuclear antibodies (ANAs) or other specific antibodies (eg anti-Smith [Sm], Ro/SSA, La/SSB and U1 ribonucleoprotein [RNP]). It has been noted that the ANAs of some patients increase or decrease in titer over time; however, the clinical utility of this observation remains unclear.

●Interpretation of laboratory results – The most useful laboratory tests to predict an SLE flare (particularly lupus nephritis) are the onset of an increased serum titer of anti-dsDNA antibodies and a fall in complement levels (especially CH50, C3, and C4) [33-39]. Persistently low serum levels of complement C1q are also associated with activity of lupus nephritis [40,41]. However, not all patients with these serologic markers have active disease, and these markers do not necessarily predict disease exacerbation or "flares" [38]. In one study, for example, 12 percent of patients with hypocomplementemia and elevated anti-DNA antibody titers had no clinical evidence of active disease [42].

●Usage of complement activation products – Cell-bound complement activation products (CB-CAPs) are under investigation to assess SLE disease activity when other serologic markers are unhelpful.

C4d and C3d, which are generated during complement activation, are covalently bound molecules and structures in the vicinity including red blood cells (RBCs), platelets, and/or peripheral blood B/T lymphocytes. Several reports suggest that monitoring erythrocyte-bound C4d (EC4d) may be superior to following C4 and C3 antigen levels in diagnosing SLE and monitoring its clinical course [43-45]. The presence of B lymphocyte-bound C4d (BC4d) confirms the presence of an autoimmune process, and platelet-bound C4d (PC4d) is increased in patients with antiphospholipid syndrome and in patients with thrombosis due to SLE [46].

Direct measurement of complement activation may be more helpful than complement levels for establishing the diagnosis of SLE and/or monitoring the clinical course of SLE patients. This situation is particularly true for patients with anti-DNA antibodies, which are associated with complement activation. C3 and C4, which are widely used as a useful measure of SLE disease activity, are both acute phase reactants. Therefore, levels of both can rise during an SLE flare even though there is complement activation. Assessing CB-CAPs in conjunction with levels of C3, C4, and anti-DNA may help determine the presence of ongoing disease activity especially if there are changes from prior values.

Direct measurement of activation fragments such as C3a, C5a, and sC5b-9 requires specific handling, which may be difficult to replicate in an office setting. However, CB-CAPs are stable, which makes these assays more appropriate for clinical use.

Additional investigations (including longer-term studies) will be needed prior to such tests becoming routinely employed for assessing diagnosis and evaluating the response to therapy.

●Other tests of limited utility – Numerous other laboratory tests assessing disease activity have been reported; however, their utility is limited because they are either unconfirmed or not accessible for routine clinical care. Some of these investigational markers that have been shown to correlate with disease activity include vitamin D receptors, and urinary interleukin (IL) 6 [43,47-51].

Additional studies in selected patients — Monitoring for specific SLE-related organ involvement typically requires additional studies. Depending on the organ system in question, appropriate investigations such as electrocardiogram, lung function tests, radiographs of affected areas, computed tomography (CT) scans, and renal or other organ (eg, skin) biopsies may be required to further evaluate the abnormalities detected on clinical assessment.

Disease activity and damage indices — Several validated indices have been developed for research purposes to measure disease activity or damage, and their incorporation into clinical practice is limited by the time needed to complete them [52]. All of the indices use a combination of history, examination, and laboratory data.

●Disease activity indices – The Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) is a scoring systems for global disease activity [53,54]. The SLEDAI-2K does not capture improving or worsening, and does not include severity within a specific organ system. However, activity categories have been defined on the basis of the score, and a score of >5 is associated with a probability of initiating therapy in >50 percent of cases [55]. Other assessment scales that assess disease activity in a single organ include the British Isles Lupus Assessment Group-2004 (BILAG-2004) [56]. While the BILAG can assess single organs, it provides information on multiple systems and can be used in a composite form.

Clinical trials are also using combinations of indices to create composite assessment measures for determining trial outcomes. Examples include the Systemic Lupus Erythematosus Response Index (SRI), used in the pivotal belimumab trials; and the BILAG-based Combined Lupus Assessment (BICLA), used in a trial of epratuzumab [57,58].

●Damage indices – A damage index score is a measure for chronic damage and is typically used in clinical research for its prognostic value. The Systemic Lupus International Collaborating Clinics American College of Rheumatology damage index (SLICC/ACR-DI) is an example of a tool that measures accumulated damage that has occurred since disease onset [59,60]. Damage can reflect the effects of either disease activity or treatment. Damage scores are mainly limited for use in clinical research for prognostic purposes [61].

MANAGEMENT

General measures — While the therapeutic approach is highly variable on an individual level, there are some general principles that apply to all patients.

●Photoprotection – Exposure to ultraviolet (UV) light may exacerbate or induce systemic manifestations of systemic lupus erythematosus (SLE) [62]; however, this does not occur in all patients. Approximately one-third of patients with SLE may experience a rash or reaction when exposed to sun, another third may have some form of reaction with prolonged exposure, and another third do not experience a reaction. In general, most patients should avoid exposure to direct or reflected sunlight, and other sources of UV light (eg, fluorescent and halogen lights). Sunscreens that block both UV-A and UV-B and have a sun protection factor (SPF) ≥55 are suggested. Medications that can cause photosensitivity should also be avoided in patients with SLE (table 1). (See "Overview of cutaneous lupus erythematosus", section on 'Management'.)

●Diet and nutrition – Limited data exist concerning the effect of dietary modification in SLE. However, a conservative approach is to recommend a balanced diet consisting of carbohydrates, proteins, and fats. Additional considerations regarding diet and nutrition in patients with SLE include the following:

•Vitamins are rarely needed when patients eat a balanced diet. However, a daily multivitamin should be taken by patients who are not able to obtain an adequate diet.

•The majority of patients with SLE have low serum levels of 25-hydroxyvitamin D (calcidiol) [63], probably due, at least in part, to avoidance of sun exposure and/or use of sunscreen products. Vitamin D levels should be monitored periodically and patients with low vitamin D levels should be treated with supplemental vitamin D. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

•In patients with hypertension and/or nephritis, dietary measures such as salt restriction may be required. (See "Salt intake and hypertension" and "Diet in the treatment and prevention of hypertension".)

●Exercise – Inactivity produced by acute illness causes a rapid loss of muscle mass, bone demineralization, and loss of stamina resulting in a sense of fatigue. This can usually be managed with isometric and graded exercise [64,65]. (See "Exercise prescription and guidance for adults".)

●Smoking cessation – Patients should be counseled against cigarette smoking, since it has been associated with more active disease [66,67]. Smoking adds to the baseline increased risk of accelerated atherosclerosis with coronary heart disease in those with SLE [68,69]. There is also evidence to suggest that smoking diminishes the efficacy of hydroxychloroquine [70,71]. (See "Overview of smoking cessation management in adults".)

●Immunizations – We advise that patients should receive appropriate immunizations prior to the institution of immunosuppressive therapies. Recommendations for vaccination of patients with systemic rheumatic diseases receiving immunosuppressive medications are summarized in the following table (table 2). Appropriate immunizations should also include coronavirus disease 2019 (COVID-19) vaccination. Additional considerations regarding the vaccine and timing of the administration for patients on selected immunosuppressive therapies is discussed in detail separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

The influenza vaccine and pneumococcal vaccines are safe, but resultant antibody titers are somewhat less in patients with SLE than in controls [72-74]. The quadrivalent human papilloma virus (HPV) vaccine has also been shown to be safe and reasonably effective in patients with stable SLE, without increasing disease activity or flares [75]. The hepatitis B vaccine also appears to be safe in patients with stable SLE [76]. Use of glucocorticoids, such as prednisone, or other immunosuppressive agents may contribute to the blunted antibody response. (See "Glucocorticoid effects on the immune system", section on 'Impact on vaccination'.)

Approach to drug therapy — The choice of drug therapy for SLE is highly individualized and depends on the predominant symptoms, organ involvement, response to previous therapy, and disease activity and severity. Adverse effects of individual therapeutic agents and patient preferences must also be taken into consideration when determining therapy. Family planning is also important to take into account when making treatment decisions. (See "Approach to contraception in women with systemic lupus erythematosus".)

Hydroxychloroquine for all patients — For all patients with SLE with any degree and type of disease activity, we recommend treatment with hydroxychloroquine. Hydroxychloroquine is available as a 200 mg tablet. Patients who weigh more than 80 kg can receive the standard daily dose of 400 mg daily. However, for patients who weigh less than 80 kg, the dose must be adjusted for a maximum daily dose of 5 mg/kg/day of actual body weight. Dosing may be once daily if tolerated. Additional information regarding the dosing of hydroxychloroquine is discussed in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Administration, dosing, and monitoring'.)

Data from observational studies and small randomized trials support that the benefits of hydroxychloroquine or chloroquine in SLE are broad. Hydroxychloroquine has been shown to have a positive impact on patient survival [77-80]. In a meta-analysis of 21 studies, hydroxychloroquine was associated with a reduction in overall mortality (pooled hazard ratio [HR] 0.46, 95% CI 0.38-0.57), even among patients with a history of lupus nephritis (HR 0.37, 95% CI 0.25-0.54) [81]. In addition, evidence from two small randomized trials and observational studies suggest that hydroxychloroquine reduces flare rates [82-85]. In a study of 55 patients with clinically stable SLE who were all on hydroxychloroquine, patients who were randomly assigned to receive placebo rather than continuing on hydroxychloroquine were more likely to experience a disease flare during the six-month follow-up period (73 versus 35 percent; HR 2.5, 95% CI 1.08-5.08) [83]. Hydroxychloroquine also reduces constitutional symptoms, musculoskeletal manifestations, and mucocutaneous manifestations [82,86,87]. Other potential benefits of hydroxychloroquine include a reduction in thrombotic events, organ damage accrual, and cancer [77,82,88-94].

Antimalarials are generally well tolerated and serious side effects are rare. However, the risk of vision-threatening toxic retinopathy remains a major concern but can be avoided when using the appropriate doses along with routine ocular monitoring. Hydroxychloroquine has also been associated with QTc interval prolongation, particularly in patients taking other QT-prolonging medications (table 3). Additional information regarding the potential adverse effects of hydroxychloroquine is presented separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects'.)

Laboratory tests to check levels of hydroxychloroquine and its metabolites are available, and there has been an interest in testing to identify patients who are nonadherent. However, practice varies, and the role of blood level testing is discussed separately. (See "Antimalarial drugs in the treatment of rheumatic disease".)

Additional therapy varies from patient to patient and based upon the severity of disease and the major organ system involvement.

Escalation of therapy based on disease activity and severity — In addition to the use of hydroxychloroquine, the need for additional therapy is generally guided by the predominant symptoms and organ involvement as well as the disease severity. While there is no single approach, we present examples below:

●Mild disease – Patients with mild disease may have predominantly skin (eg, a malar rash) and joint (eg, arthralgias or arthritis) involvement and may also feel increasingly fatigued. Laboratory evaluation to assess for disease activity may be unremarkable or reveal a mild leukopenia. Other than initiating treatment with hydroxychloroquine (if the patient is not already taking it), such patients may require no additional therapy. Alternatively, the patient may require short-term use of nonsteroidal antiinflammatory drugs (NSAIDs) or prednisone 7.5 mg daily (or equivalent).

The management of cutaneous and joint involvement of SLE are discussed in detail separately. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus" and "Overview of cutaneous lupus erythematosus".)

●Moderate disease – Patients with moderate disease severity may be described as having significant but non-organ-threatening disease (eg, constitutional, cutaneous, musculoskeletal, or hematologic). Patients usually respond to hydroxychloroquine plus short-term therapy with 5 to 15 mg of prednisone (or equivalent) daily. Hydroxychloroquine takes approximately three months for a clinical effect to be observed. Prednisone is usually tapered once hydroxychloroquine has taken effect. A glucocorticoid-sparing immunosuppressive agent (eg, azathioprine, belimumab, or anifrolumab) is often required to control symptoms.

●Severe disease – A patient with organ-threatening manifestations (eg, renal and central nervous system [CNS] involvement) generally requires an initial period of intensive immunosuppressive therapy (induction therapy) to control the disease and halt tissue injury. As an example, such a patient may develop renal insufficiency and significant proteinuria due to lupus nephritis. Laboratory evaluation may reveal a low C3, C4, elevated anti-double-stranded DNA (dsDNA) antibodies, and elevated acute phase reactants. Patients are usually treated for a short period of time with high doses of systemic glucocorticoids (eg, intravenous "pulses" of methylprednisolone, 0.5 to 1 g/day for three days in acutely ill patients, or oral prednisone 1 to 2 mg/kg/day in more stable patients) used alone or in combination with other immunosuppressive agents. There is a paucity of data to support the use of intravenous "pulse" versus daily oral glucocorticoids [95]. One of the major advantages of glucocorticoid therapy is that it rapidly reduces inflammation, thereby helping to achieve disease control. However, attempts to minimize exposure must always be made, given the long-term adverse effects. (See "Major adverse effects of systemic glucocorticoids".)

Additional immunosuppressive agents are typically added as glucocorticoid-sparing therapy and may include mycophenolate, cyclophosphamide, or rituximab and may require hospitalization. This initial therapy is subsequently followed by a longer period of less intensive, and ideally less toxic, maintenance immunosuppressive therapy to consolidate remission and prevent flares. During this phase of treatment, the dose of prednisone or equivalent is reduced while monitoring clinical and laboratory measures of disease activity.

Treatment of specific SLE manifestations — There is limited evidenced-based literature for managing organ-specific manifestations outside of the kidney and skin. Despite this, the choice of therapy is generally guided by the predominant symptoms and organ involvement.

●Constitutional symptoms – Constitutional symptoms such as fatigue and fever are common among patients with SLE:

•Fatigue among patients with SLE is often caused by a host of possibilities not directly associated with SLE. These include depression, deconditioning, disordered sleep, fibromyalgia, and iron-deficiency anemia. Once these causes of fatigue have been excluded or addressed, fatigue in patients who do not have organ-threatening SLE involvement may be reduced by low-dose glucocorticoids and hydroxychloroquine [96]. There are also data to suggest that belimumab may have beneficial effects on fatigue [97].

•An underlying infection may be the cause of fever in a patient with SLE, particularly among those receiving significant immunosuppressive agents. After an infection has been excluded, fever associated with SLE activity should respond to NSAIDs, acetaminophen, and/or low to moderate doses of glucocorticoids. Fever that does not respond to such therapy further raises the suspicion of an infectious and/or drug-related etiology. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

The management of patients with cutaneous, musculoskeletal, kidney, gastrointestinal, pulmonary, cardiovascular, hematologic, and/or neurologic involvement is discussed separately in the following topic reviews:

●Cutaneous involvement – (See "Overview of cutaneous lupus erythematosus" and "Initial management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus" and "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy".)

●Raynaud phenomenon – (See "Treatment of Raynaud phenomenon: Initial management" and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)

●Arthritis and musculoskeletal manifestations – (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus".)

●Kidney involvement – (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis" and "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy" and "Lupus nephritis: Therapy of lupus membranous nephropathy" and "Kidney transplantation in adults: Issues related to lupus nephritis".)

●Gastrointestinal involvement – (See "Gastrointestinal manifestations of systemic lupus erythematosus".)

●Pulmonary involvement – (See "Pulmonary manifestations of systemic lupus erythematosus in adults".)

●Cardiac involvement – (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Coronary artery disease in systemic lupus erythematosus".)

●Hematologic manifestations – (See "Hematologic manifestations of systemic lupus erythematosus".)

●Neurologic and neuropsychiatric manifestations – (See "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system" and "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus".)

Considerations regarding specific therapies

Anifrolumab — Anifrolumab, a monoclonal antibody to the type I interferon (IFN) receptor, has received approval by the US Food and Drug Administration (FDA) for the treatment of patients with moderate to severe SLE (but without severe active lupus nephritis or neuropsychiatric SLE) who are receiving standard therapy. Anifrolumab blocks the activity of type I IFNs, including IFN-alpha, IFN-beta, and IFN-kappa, which are cytokines that are elevated in many patients with SLE, and mutations in these IFN-signaling pathways have been linked to disease susceptibility [98]. Anifrolumab's role in therapy is still being defined, but there appears to be a particular benefit for patients with skin and joint involvement [99].

FDA approval was based on findings from three randomized trials demonstrating that more patients had reductions in overall disease activity and glucocorticoid dose with the addition of anifrolumab to standard therapy compared with placebo [100-102]. In the initial phase 3 trial including 457 patients with SLE, the primary endpoint was not met, as patients in the anifrolumab group achieved a similar SLE responder index 4 (SRI-4) response (a composite measure of improvement) at 52 weeks when compared with those receiving placebo [102]. However, there appeared to be a trend towards benefit in other endpoints including improvement in the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), which may be a more sensitive test for detecting clinical change, as well as a reduction in glucocorticoid dose.

In a subsequent phase 3 trial with 362 patients with SLE, 47 percent of patients in the anifrolumab group showed improvement as measured by the BICLA compared with 31 percent in the placebo group (difference 16.3 percentage points, 95% CI 6.3-26.3) at 52 weeks [101]. More patients in the treatment group were also able to reduce their glucocorticoid dose. Adverse effects in the anifrolumab group included herpes zoster in 7 percent and bronchitis in 12 percent [101], but in general, it appears to have a good safety profile [103].

An analysis of patients enrolled in both trials indicated that patients treated with anifrolumab achieved a lupus low disease activity state (LLDAS) earlier, and remained in LLDAS longer, than patients treated with placebo [104].

Rituximab — The role of rituximab, a B cell-depleting chimeric monoclonal antibody, in the treatment of patients with SLE remains uncertain [105]. Several uncontrolled observational studies have reported efficacy of rituximab in the treatment of SLE patients with and without lupus nephritis who have failed to respond to standard treatment [106-110]. In addition, a systematic review of SLE patients with active disease refractory to glucocorticoids and/or immunosuppressive drugs assessed the efficacy and safety of rituximab on non-renal outcomes and found short-term improvements in measures of disease activity, immunologic parameters (eg, complement levels and dsDNA), arthritis, and thrombocytopenia, as well as a glucocorticoid-sparing effect [111]. By comparison, the EXPLORER and LUNAR trials, which were both randomized trials, found that rituximab did not provide any significant benefit compared with controls [112,113]. However, limitations in the study design of the both the EXPLORER and LUNAR trials may have prevented a determination of benefit. In each of the trials, both comparator groups were receiving high doses of glucocorticoids in addition to immune suppression; thus, it was not possible to determine the efficacy of rituximab.

The LUNAR trial and the use of rituximab in patients with lupus nephritis is discussed in detail separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Combination regimens'.)

Agents under investigation — A number of other therapeutic approaches have been tried or are under investigation in SLE. These include B-cell-targeted therapy (such as atacicept), anti-interleukin (IL) 6 receptor, iberdomide (cereblon E3 ligase modulator) [114], low-dose IL-2 [115], obinutuzumab (anti-CD20 monoclonal antibody) [116,117], daratumumab (anti-CD38 monoclonal antibody) [118,119], anti-CD40 monoclonal antibody [120], and litifilimab (blood dendritic cell antigen 2 inhibitor) [121,122]. The use of autologous CD19 chimeric antigen receptor T (CAR T) cells has also been described in patients with refractory SLE [123,124]. Janus kinase inhibitors including baricitinib [125,126] or ustekinumab [127] do not appear to be effective in the management of SLE. Information concerning ongoing trials in the United States of agents for patients with SLE can be found at www.clinicaltrials.gov.

Monitoring response to therapy — The frequency with which monitoring laboratory tests are performed is tailored to each patient. Factors that should be taken into account when determining the frequency of visits include the history of the patient's prior symptoms, current disease activity status, disease severity, and frequency and severity of prior disease flares. As an example, a patient with active lupus nephritis may require laboratory tests every one to two weeks to monitor and guide therapy. By contrast, another patient with previously active nephritis, but whose SLE is quiescent, may be tested every three to four months.

For most patients with SLE, we favor an approach in which patients are monitored every three to four months, and therapy is adjusted if there are signs of clinical worsening of the disease. Although expert groups recommend that SLE patients with stable disease be monitored less frequently (eg, at up to six-month intervals) [128], there is evidence that these patients benefit from closer follow-up at three- to four-month intervals [24,129]. A study including over 500 SLE patients with mild or inactive disease found that one in four patients followed over a two-year period will have a clinically silent laboratory abnormality (eg, low complement or hematuria) that could lead to a change in management [130]. The average length of time between visits in the aforementioned study was 3.8 months, highlighting the importance of regular patient monitoring.

However, most expert groups agree with monitoring all SLE patients at significant risk for developing lupus nephritis on at least a three-month basis in an effort to detect early signs of kidney disease [4,131]. Risk factors for developing lupus nephritis include those who have elevated levels of antibodies to dsDNA [132].

Other treatment considerations

Treatment of comorbid conditions — Accelerated atherosclerosis, pulmonary hypertension, and antiphospholipid syndrome, Raynaud phenomenon, Sjögren's disease, as well as osteopenia or osteoporosis, are among the comorbid conditions which can be treated and for which screening tests are appropriately used. These comorbid disorders, for which patients with SLE have an increased risk, include [3]:

●Accelerated atherosclerosis – Modifiable risk factors for coronary heart disease can be addressed using guidelines for the general population such as smoking cessation, weight loss through dietary modification and exercise, use of statins, and optimal blood pressure control. (See "Coronary artery disease in systemic lupus erythematosus", section on 'Prevention and treatment'.)

●Pulmonary hypertension – If pulmonary hypertension is documented, management is similar to the patient with idiopathic pulmonary hypertension. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

●Antiphospholipid syndrome – The indications for therapy and specific management issues are the same in patients with antiphospholipid syndrome with or without concurrent SLE. (See "Management of antiphospholipid syndrome".)

●Raynaud phenomenon – The management of Raynaud phenomenon is discussed in detail separately. (See "Treatment of Raynaud phenomenon: Initial management".)

●Sjögren's disease – Sjögren's disease may occur in association with SLE. The management of Sjögren's disease is discussed separately. (See "Overview of the management and prognosis of Sjögren's disease".)

●Osteopenia or osteoporosis – Osteoporosis or osteopenia is a significant problem in patients with SLE, particularly in patients receiving therapy with glucocorticoids. The treatment of this condition is discussed separately. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus".)

●Fibromyalgia – Fibromyalgia can affect approximately 30 percent of patients with SLE. The treatment of fibromyalgia discussed separately. (See "Treatment of fibromyalgia in adults" and "Overview of chronic widespread (centralized) pain in the rheumatic diseases", section on 'Systemic lupus erythematosus and Sjögren's disease'.)

Issues with specific therapies

●Allergies – Allergies to antibiotics are more common among patients with SLE, with up to 30 percent of patients having an allergy to sulfonamide-containing antibiotics that include sulfamethoxazole (in trimethoprim-sulfamethoxazole [TMP-SMX]) and other less commonly used sulfonylarylamine antimicrobials (table 4) [133-135]. The most common allergic reaction is skin rash [133]. Sulfonamide-containing antimicrobials have also been associated with SLE exacerbations and should therefore be avoided, if possible [133,136]. In the general population, nonantimicrobial drugs that contain a nonarylamine sulfonamide (eg, diuretics, sulfonylurea hypoglycemics, a few NSAIDs) (table 5) are generally not cross-reactive with sulfonamide antimicrobial hypersensitivity and, in the author's experience, are far less likely to be associated with exacerbations of SLE. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Nonantimicrobial sulfonamides'.)

●Drug-induced lupus – By contrast, medications that cause drug-induced lupus, such as procainamide and hydralazine, do not cause exacerbations of idiopathic SLE. This observation is a presumed reflection of the pathogenetic differences between the two disorders. However, while we use most other agents that may cause drug-induced lupus, we avoid the use of minocycline in patients with established (idiopathic) SLE. (See "Drug-induced lupus".)

●Glucocorticoids – Unresponsiveness to prednisone is poorly studied and not well documented in the literature, but has been observed and described by clinicians, and may affect patients with SLE [137]. Estimates as high as approximately 15 percent of the general population may not adequately convert prednisone to its active metabolite. Patients with liver disease are also thought to be impacted by this problem. Thus, some clinicians favor using methylprednisolone rather than prednisone in patients with SLE who are suspected to have liver disease. A limited or poor response to prednisone should also prompt consideration of a switch to an equivalent dose of methylprednisolone. In addition, methylprednisolone is generally preferred over prednisone for pediatric patients with SLE whose liver is presumed to be immature.

●Radiation therapy – Radiation therapy for the treatment of malignancy should not be withheld or avoided in patients with SLE. In the past, several case reports of increased toxicity following therapeutic radiation in patients with systemic rheumatic diseases made radiation oncologists wary of treating patients with SLE [138-141]. However, additional observational data have also suggested that radiation therapy in patients with SLE is not associated with an increased risk of toxicity [142-145]. An exception might be patients with SLE who also have overlapping features of systemic sclerosis (SSc) may be at increased risk of induction of pulmonary fibrosis, and treatment decisions should be made on an individual basis with careful consideration of the potential risks and benefits of therapy.

Pregnancy and contraception — Pregnancy should be avoided during active disease (especially with significant organ impairment) due to the high risk of miscarriage and exacerbation of SLE. Women with SLE should be counseled not to become pregnant until the disease has been quiescent for at least six months. A detailed discussion on pregnancy in patients with SLE is presented separately. (See "Pregnancy in women with systemic lupus erythematosus".)

Issues related to contraception in patients with SLE are discussed separately. (See "Approach to contraception in women with systemic lupus erythematosus".)

Assessment of adherence to therapy — Nonadherence to medications appears to be relatively common among patients with SLE [146]. In some cases, suspected treatment resistance can be related to nonadherence rather than actual resistance to immunosuppressive therapy. An approach assessing adherence among patients with SLE is discussed in detail separately. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy", section on 'Assessment of patient adherence to therapy'.)

PROGNOSIS — Systemic lupus erythematosus (SLE) can run a varied clinical course, ranging from a relatively benign illness to a rapidly progressive disease with fulminant organ failure and death.

●Mortality rates – The five-year survival rate in SLE has dramatically increased since the mid-20^th century, from approximately 40 percent in the 1950s to greater than 90 percent since the 1980s [147-151]. The improvement in patient survival is probably due to multiple factors including increased disease recognition with more sensitive diagnostic tests [152], earlier diagnosis or treatment, the inclusion of milder cases, increasingly judicious therapy, and prompt treatment of complications [153].

Despite these improvements, patients with SLE still have mortality rates ranging from two to five times higher than that of the general population [154,155]. Based on mortality data from the United States Centers for Disease Control and Prevention (CDC) from 2000 to 2015, SLE ranked among the top 20 leading causes of death in females between the ages of 5 and 64 [156]. In another large population-based study in the United States, mortality risk from SLE was higher among women, African Americans, and residents of the South [157].

●Causes of death – The major causes of death in the first few years of illness are active disease (eg, central nervous system [CNS] and kidney disease) or infection due to immunosuppression. Achieving remission or a low disease activity state is associated with a reduced risk of death [158]. Causes of late death include cardiovascular disease, complications of SLE (eg, end-stage kidney disease), and treatment complications [153,159-165].

Prognostic factors associated with increased mortality in SLE include [148,149,161,166-173]:

•Kidney disease (especially diffuse proliferative glomerulonephritis)

•Hypertension

•Male sex

•Young age

•Older age at presentation

•Low socioeconomic status

•Being a Black person

•Presence of antiphospholipid antibodies

•Antiphospholipid antibody syndrome

•High overall disease activity

The frequency of the different causes of death is best illustrated by a 2014 meta-analysis of 12 studies that included 27,123 patients with SLE (4993 observed deaths) [174]. This analysis reported an overall threefold increased risk of death in patients with SLE (standardized mortality rate [SMR] 2.98, 95% CI 2.32-3.83) when compared with the general population. The risks of death due to cardiovascular disease, infection, and kidney disease were significantly increased. Mortality due to malignancy was not found to be increased, while patients with kidney disease were found to have the highest mortality risk (SMR 7.90, 95% CI 5.5-11.0).

●Morbidity – Despite a reduction in the risk of premature death, patients with SLE are at risk for significant morbidity due both to active disease and to the side effects of drugs such as glucocorticoids and cytotoxic agents [175].

Factors that may be associated with a shorter delay between disease onset and organ damage include [176,177]:

•Being an Asian or Hispanic person

•Greater disease activity

•A history of thrombotic events

•Glucocorticoid use of less than 10 mg per day

●Glucocorticoid effects – Glucocorticoid use at doses equivalent to prednisone ≥10 mg/day has been associated with a longer time from SLE onset to organ damage, but as noted above, long-term use of higher doses of glucocorticoids has significant risks that must be considered. However, the relationship between glucocorticoid dose and organ damage is not well defined, and there are conflicting results.

A cohort of 525 patients with SLE from a single academic medical center was followed for up to 10 years on varying doses of prednisone, and the findings suggested that low doses of prednisone do not result in a substantially increased risk of irreversible organ damage [178]. However, glucocorticoid-induced avascular necrosis of the hips and knees, osteoporosis, fatigue, and cognitive dysfunction have become particularly important problems as patients live longer with their illness with a concomitant increase in total glucocorticoid exposure [179]. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

●Hospitalization – Patients with SLE experience high rates of hospital admission and readmission. In the United States, more than half of Medicare SLE hospitalizations occur in patients younger than 65, who qualify for Medicare due to chronic disability or end-stage kidney disease [180]. In a study of 10,866 Medicare hospitalizations among patients with SLE, the 30-day rehospitalization rate was highest among young adults (aged 18 to 36 years old) [181]. The rehospitalization rate for young adults with SLE was higher than the rehospitalization rate for young adults with other diagnoses (36 versus 26 percent). Predictors of rehospitalization for all Medicare patients with SLE included coagulopathy, congestive heart failure, illicit drug use, fluid and electrolyte disorders, and paralysis.

In another study of 132,400 hospitalized adults with SLE, 14.3 percent were readmitted within 30 days of discharge [182]. The factors associated with the highest odds of readmission included autoimmune hemolytic anemia (odds ratio [OR] 1.86), glomerular disease (OR 1.27), pericarditis (OR 1.35), heart failure (OR 1.34), age 18 to 30 years versus age greater than 65 years (OR 1.28), and Medicare (OR 1.20) or Medicaid (OR 1.26) insurance. Readmissions of SLE patients with Medicaid may be tied to poor access to care and sociodemographics [183].

●Malignancy risk – The overall risk of malignancy is increased among patients with SLE. In a study of adults who used Finland's National Health Insurance, the incidence ratio for any malignancy compared with a population without SLE was 1.4 (95% CI 1.1-1.8) [184].

Patients with SLE have a three- to fourfold increased risk of non-Hodgkin lymphoma compared with the general population [185]. Non-Hodgkin lymphoma in patients with SLE often has an aggressive histologic subtype (eg, diffuse large B-cell lymphoma), which is associated with an increased risk of death [186,187].

Patients with SLE may also be at increased risk of cancer of the vulva, lung, thyroid, and hepatobiliary tract, although this has not been well established [185,188-195].

Although the overall risk of death due to malignancy does not appear to be increased in SLE patients, the risk of death due to specific malignancies is significantly increased among SLE patients when compared with the general population [163,184,185,188-195].

●Likelihood of clinical remission – After appropriate therapy, remission of at least one-year duration is achieved by 7 to 25 percent of patients with SLE [12,196]. However, only 2 to 7 percent of patients will achieve remission lasting for five years or longer [11,12]. Half of patients who relapse after achieving remission will not achieve a subsequent remission [196]. Predictors of a sustained (ie, longer than three years) drug-free remission include [11,12,16,196-198]:

•Being a White person (adjusted hazard ratio [HR] 2.16)

•Age >32 at diagnosis (adjusted HR 1.92)

•Absence of kidney involvement (adjusted HR 2.55)

•Absence of antiphospholipid antibody syndrome (adjusted HR 4.92)

Definitions for clinical remission are discussed separately. (See 'Definitions' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus" and "Society guideline links: Cutaneous lupus erythematosus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Lupus (The Basics)")

●Beyond the Basics topics (see "Patient education: Systemic lupus erythematosus (Beyond the Basics)" and "Patient education: Systemic lupus erythematosus and pregnancy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals and overview of therapy – The goals of therapy for systemic lupus erythematosus (SLE) patients are to achieve remission or low disease activity, prevent organ damage, minimize drug toxicity, and improve quality of life. Treatment of SLE is individualized based upon patient preferences, clinical manifestations, disease activity and severity, and comorbidities (See 'Goals and overview of therapy' above.)

●Assessment of disease activity – Given the heterogeneity of disease presentation and clinical course among patients with SLE, an assessment of disease activity should be performed at each clinic visit. In clinical practice, disease activity and severity are assessed using a combination of clinical history, physical examination, laboratory and imaging studies for specific organs, and serologic tests. (See 'Assessment of disease activity' above.)

•Laboratory evaluation – We typically check the following laboratory tests when assessing disease activity in patients with SLE: complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), spot urine protein and creatinine, serum creatinine, estimated glomerular filtration rate (eGFR), anti-double-stranded DNA (dsDNA), and complement levels (C3 and C4). (See 'Laboratory evaluation' above.)

•Additional studies in selected patients – Monitoring for specific SLE-related organ involvement typically requires additional studies. Depending on the organ system in question, appropriate investigations such as electrocardiogram, lung function tests, radiographs of affected areas, CT scans, and renal or other organ (eg, skin) biopsies may be required. (See 'Additional studies in selected patients' above.)

●Management

•General measures – Several nonpharmacologic and preventive interventions important in the management of SLE include photoprotection, diet and nutrition, exercise, smoking cessation, and maintenance of appropriate immunizations. (See 'General measures' above.)

•Hydroxychloroquine for all patients – Among patients with SLE with any degree and type of disease activity, we recommend administering hydroxychloroquine or chloroquine (Grade 1B), unless a contraindication exists. (See 'Hydroxychloroquine for all patients' above.)

•Escalation of therapy based on disease activity and severity – Additional therapy is based upon the severity of disease and the combination of manifestations. While there is no single approach, we present examples below (see 'Escalation of therapy based on disease activity and severity' above):

-Mild disease – Patients with mild disease (eg, with skin, joint, and mucosal involvement) are administered hydroxychloroquine. Such patients may require no additional therapy. Alternatively, the patient may require short-term use of nonsteroidal antiinflammatory drugs (NSAIDs), and/or low-dose glucocorticoids (eg, ≤7.5 mg prednisone equivalent per day).

-Moderate disease – Patients with moderate disease may be described as having significant but non-organ-threatening disease (eg, constitutional, cutaneous, musculoskeletal, or hematologic). Patients usually respond to hydroxychloroquine or chloroquine plus short-term therapy with 5 to 15 mg of prednisone (or equivalent) daily. Prednisone is usually tapered once hydroxychloroquine has taken effect. A glucocorticoid-sparing immunosuppressive agent (eg, azathioprine, belimumab, or anifrolumab) is often required to control symptoms.

-Severe disease – Patients with organ-threatening manifestations (eg, renal and central nervous system [CNS] involvement) generally require an initial period of intensive immunosuppressive therapy (induction therapy) to control the disease and halt tissue injury. Patients are usually treated for a short period of time with high doses of systemic glucocorticoids (eg, 1 to 2 mg/kg/day of prednisone or equivalent or intermittent intravenous "pulses" of methylprednisolone) used alone or in combination with other immunosuppressive agents (eg, mycophenolate or cyclophosphamide). This initial therapy is subsequently followed by a longer period of less intensive and, ideally, less toxic maintenance therapy to consolidate remission and prevent flares. During this phase of treatment, the dose of prednisone or equivalent is reduced while monitoring clinical and laboratory measures of disease activity.

●Monitoring response to therapy – The frequency with which monitoring laboratory tests are performed is tailored to each patient. However, for most patients with SLE, we favor an approach in which patients are monitored every three to four months, and therapy is adjusted if there are signs of clinical worsening of the disease. (See 'Monitoring response to therapy' above.)

●Other treatment considerations – Other important treatment considerations include treatment of comorbid conditions, issues related to specific medications (eg, with sulfonamide-containing antibiotics), and precautions around pregnancy and contraception. (See 'Other treatment considerations' above.)

●Prognosis – SLE can run a varied clinical course, ranging from a relatively benign illness to a rapidly progressive disease with fulminant organ failure and death. Clinical remission after appropriate therapy is uncommon, and, when it is achieved, it is often not sustained. (See 'Prognosis' above.)

●Morbidity and mortality – Patients with SLE have mortality rates ranging from two to five times higher than that of the general population. The major causes of death in the first few years of illness are active disease (eg, CNS and kidney) or infection due to immunosuppression, while causes of late death include complications of SLE (eg, endstage kidney disease), treatment complications, and cardiovascular disease. Patients are also at risk for significant morbidity due to both active disease and the side effects of drugs such as glucocorticoids and cytotoxic agents. (See 'Prognosis' above.)