28.5.2014 Overview of the therapy and prognosis of systemic lupus erythematosus in adults

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Official reprint from UpToDate www.uptodate.com ©2014 UpToDate

AuthorsPeter H Schur, MDDaniel J Wallace, MD

Section EditorDavid S Pisetsky, MD, PhD

Deputy EditorMonica P Ramirez, MD, MPH

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

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2014. | This topic last updated: Sep 26, 2013.

INTRODUCTION — Systemic lupus erythematosus (SLE) is a chronic, occasionally life-threatening, multisystem

disorder. Patients suffer from a wide array of symptoms and have a variable prognosis that depends upon the

severity and type of organ involvement. The diagnosis of SLE should be confirmed prior to initiating treatment (table

1). (See "Diagnosis and differential diagnosis of systemic lupus erythematosus in adults".)

Due to the uncertain course, effective treatment requires ongoing patient-doctor communication to correctly

interpret laboratory tests, to alleviate symptoms, to prevent and treat relapses, to lessen side effects related to drug

therapy, to improve adherence with medications, and to coordinate care with the patient’s primary care provider [1-

6].

This topic will review the general issues related to the treatment and prognosis of patients with SLE. The treatment

of specific organ involvement is discussed separately. (See appropriate topic reviews.)

DETERMINATION OF DISEASE ACTIVITY AND SEVERITY — An effective therapeutic regimen first requires

confirmation of the diagnosis and the accurate determination of both disease activity and severity [7-11]. Disease

activity usually refers to the degree of inflammation, while the degree of severity depends upon the level of organ

dysfunction and upon the organ’s relative importance. The degree of irreversible organ dysfunction has been referred

to as the “damage index” [12].

The presence of severe organ dysfunction does not necessarily imply ongoing inflammation. As an example,

marked proteinuria and a decreasing glomerular filtration rate may result either from active inflammation or from

scarred nephrons in the absence of active inflammatory disease. The ability to differentiate between these two

possibilities is extremely important, since immunosuppressive therapy is not indicated in the latter setting. (See

"Therapy of diffuse or focal proliferative lupus nephritis".)

Clinically useful markers of activity — Disease activity is assessed using a combination of the clinical history,

physical examination, organ-specific functional tests, and serologic studies [7-11,13-15]. Examples include:

®

®

Active systemic lupus erythematosus (SLE) (particularly lupus nephritis) is often preceded by a rise in

immunoglobulin G (IgG) anti-double-stranded deoxyribonucleic acid (dsDNA) titers [16-20], by a fall in

complement levels (especially CH50, C3, and C4) [17,19,20], and by an elevation in complement split and

activation products [17,19-21].

●

Persistently low serum levels of complement C1q are associated with continued activity of proliferative

glomerulonephritis [22].

●

Increases in the erythrocyte sedimentation rate (ESR) and in the serum C-reactive protein (CRP)

concentration are also commonly seen within this setting [23-26], and, in one study, increases in the CRP

were associated with a broad range of particular clinical features and with disease activity or organ damage in

certain systems [27]. The association of increased CRP with disease activity was noted particularly with

constitutional, eye, pulmonary, gastrointestinal, and neurologic disease activity, but elevated CRP was not

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However, not all patients with these serologic markers have active disease, and these markers do not necessarily

predict disease exacerbation or “flares” (see 'Definition of flares' below) [25] . In one study, for example, 12 percent

of patients with hypocomplementemia and elevated anti-DNA antibody titers had no clinical evidence of active

disease [30]. We favor an approach in which such patients are closely monitored; therapy is adjusted if there are

signs of clinical worsening of the disease.

Definition of flares — 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 definitions have

incorporated a combination of results from serologic measures and disease activity indices. Flares are generally

qualified by severity, with moderate or severe flares being the most clinically significant. Most clinicians agree that

a moderate or severe flare refers to a measurable increase in disease activity that is clinically meaningful enough to

result in a change in therapy [31-33]. A challenge in clinical practice is to stratify patients at risk for disease flares.

We use serologic measures of disease activity in the context of the clinical presentation and organ domain

involvement to evaluate for a disease flare. (See 'Clinically useful markers of activity' above.)

Frequency of laboratory testing — The frequency with which monitoring laboratory tests are performed is tailored

to each patient. In general, patients with more active disease are monitored more frequently, while those with

inactive disease require less frequent monitoring. As examples:

The following laboratory tests are suggested for monitoring in a patient with a previous history of renal involvement

who is currently free of proteinuria and who has a normal creatinine clearance:

For patients without a history of lupus nephritis, the spot (untimed) urine protein and creatinine, as well as the

serum albumin, are unnecessary.

Investigational markers — Numerous investigations of other immunologic tests as indicators of disease activity

have been reported, including antibodies to C1q and to nucleosomes, complement activation products, soluble T-

cell activation markers, serum levels of various cytokines and cytokine receptors, angiogenic factors, adhesion

molecules, chemokines, and cell surface makers of immunologic activation (eg, erythrocyte- or reticulocyte-bound

associated with an index of organ damage [28]. There are conflicting data on the diagnostic value of a marked

elevation of CRP in distinguishing active lupus from infection [24,29], but a markedly elevated level of CRP in a

patient with SLE should raise the suspicion for infection [26].

A patient with active lupus nephritis may have a battery of tests done once weekly.●

For someone with a reduction in glomerular filtration rate whose disease is stable and who is free of

proteinuria, testing every two to three months may be appropriate.

●

A patient with previously active nephritis, a normal glomerular filtration rate, and no proteinuria, whose SLE is

otherwise quiescent, may be tested every four to six months.

●

Someone with no history of renal involvement and with quiescent disease may be retested every 6 to 12

months.

●

Complete blood count●

Erythrocyte sedimentation rate●

C-reactive protein●

Urinalysis with examination of urinary sediment●

Spot (untimed) urine protein and creatinine●

Serum creatinine and estimated glomerular filtration rate (eGFR)●

Serum albumin●

Anti-dsDNA●

Complement (CH50, C3, and C4)●

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C4d) [20].

Gene expression profiling and proteomic approaches may eventually provide additional indices of disease activity.

As examples:

The usefulness of the investigational markers of disease activity noted above either has been unconfirmed or has

generally not been proven to be as useful as monitoring complement and anti-double stranded DNA antibodies.

Disease activity indices — A number of research protocol disease activity or damage measures or indices,

including the Systemic Lupus Erythematosus (SLE) Disease Activity Index (SLEDAI), the Safety of Estrogens in

Lupus Erythematosus: National Assessment-SLEDAI (SELENA-SLEDAI), the Systemic Lupus Activity Measure

(SLAM), the British Isles Lupus Assessment Group (BILAG), the European Consensus Lupus Activity

Measurement (ECLAM), and others, have been designed in an attempt to better monitor disease activity and to

assess trial outcomes [15,38,41-46]. They all use a combination of history, examination, and laboratory data; these

protocols may have general applicability to clinical practice if simplified. The particular outcome measure used in a

trial, even for organ-specific disease such as lupus nephritis, can influence apparent trial outcomes [47].

Clinical trials are also using combinations of indices to create composite assessment measures for determining

trial outcomes. Examples include the SRI (Systemic Lupus Erythematosus Response Index), used in the pivotal

belimumab trials, and the BICLA (BILAG-based Combined Lupus Assessment), used in a trial of epratuzumab [48].

(See 'Belimumab' below.)

GENERAL TREATMENT CONSIDERATIONS — Although the pattern and severity of organ involvement determines

specific drug therapy, a number of general issues are applicable to every patient with systemic lupus

erythematosus (SLE). We emphasize the importance of adherence to medication regimens, of maintenance of

good sleep hygiene, and of follow-through with recommended testing. Patients should also be informed of the

availability of resource information relating to the treating center and to lupus support organizations [6,49].

Sun protection — Avoid exposure to direct or reflected sunlight and other sources of ultraviolet (UV) light (eg,

fluorescent and halogen lights). Use sunscreens, preferably those that block both UV-A and UV-B, with a high skin

protection factor (SPF). A sunscreen with a SPF of 55 or greater is suggested.

Diet and nutrition — Limited data exist concerning the effect of dietary modification in SLE [50,51]. Of two studies

performed by one group of investigators, the larger trial randomly assigned 60 patients to receive either 1.8 g of

eicosapentaenoic acid (EPA) and 1.2 g of docosahexanoic acid (DHA) or placebo, daily, for 24 weeks [51]. Those

on fish oil had a significantly greater reduction in an index of disease activity (the revised SLAM [SLAM-R]) and

improvement in endothelial function, as assessed by flow-mediated arterial dilation, than did the placebo group.

These findings await independent confirmation; thus, we do not recommend fish oil supplements in the treatment of

SLE.

A conservative approach is to recommend a balanced diet consisting of carbohydrates, proteins, and fats. However,

An increased expression of genes activated by interferon in peripheral blood mononuclear cells has been

noted [34,35].

●

Active disease may be associated with a constellation of autoantibodies that can be detected using

glomerular proteomic arrays [36].

●

A proteomic approach identified a pattern of proteins that was both sensitive and specific for active nephritis

[37].

●

Increased amounts of erythrocyte-bound C4d were correlated with increased disease activity in one study [38]

but not in another [39].

●

Urinary biomarkers for nephritis include interleukin-6, neutrophil gelatinase-associated lipocalin, monocyte

chemoattractant protein, micro-ribonucleic acid (miRNA), and transforming growth factor-β [39,40]

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the diet should be modified based upon disease activity and upon the response to therapy:

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 treated with isometric and graded exercise

[57,58]. In selected refractory cases, relief can be obtained with antimalarial drugs [59].

Smoking cessation — Cigarette smoking may increase the risk of developing SLE [60], and smokers in general

have more active disease [61]. Patients should be counseled not to smoke or to quit smoking and should be

provided with help to do so. Hydroxychloroquine is less effective in smokers [61,62]. (See "Patient information:

Quitting smoking (Beyond the Basics)" and "Overview of smoking cessation management in adults".)

Immunizations — We advise that patients should receive appropriate immunizations prior to the institution of

immunosuppressive therapies. It had been previously thought that immunization could exacerbate SLE. However,

influenza vaccine and pneumococcal vaccines are safe, but resultant antibody titers are somewhat less in patients

with SLE than in controls [63,64]. 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 [65]. 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'.)

In contrast, it is inadvisable to immunize potentially immunosuppressed patients (including those treated with

glucocorticoids alone at doses equivalent to ≥20 mg/day of prednisone for more than two weeks) with live vaccines

(eg, measles, mumps, rubella, polio, varicella, and vaccinia [smallpox]) [63]. (See "Immunizations in patients with

Patients with active inflammatory disease and fever may require an increase in caloric intake.●

Glucocorticoids enhance appetite, resulting in potentially significant weight gain. Hunger can be somewhat

lessened by the ingestion of water, antacids, proton pump inhibitors, and/or histamine H2 blockers. A low

calorie diet should be instituted if there is significant weight gain.

●

Hyperlipidemia may be induced by the nephrotic syndrome or by the administration of glucocorticoids (see

"Lipid abnormalities in nephrotic syndrome") [52] . In one report, increasing the dose of prednisone by 10 mg

per day was associated with an elevation in serum cholesterol of 7.5 mg/dL (0.2 mmol/L) [53].

Patients with hyperlipidemia should be encouraged to eat a low-fat diet [54]. A lipid-lowering agent (usually a

statin) should be considered if serum cholesterol remains above the recommended values despite a change in

diet. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention".)

●

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 or who are dieting to lose weight.

●

The majority of patients with SLE have low serum levels of 25-hydroxyvitamin D (calcidiol) [55], probably due,

at least in part, to avoidance of sun exposure. Patients with low vitamin D levels should be treated with

supplemental vitamin D. (See "Musculoskeletal manifestations of systemic lupus erythematosus".)

Patients on long-term glucocorticoids and postmenopausal women should ingest 800 units of vitamin D plus

1500 mg of calcium per day and/or should ingest a bisphosphonate to minimize the degree of bone loss. (See

"Prevention and treatment of glucocorticoid-induced osteoporosis".)

●

Herbal remedies are of unproven benefit and may cause harm [56].●

In patients with hypertension and/or nephritis, dietary measures such as salt restriction may be required. (See

"Salt intake, salt restriction, and primary (essential) hypertension" and "Diet in the treatment and prevention of

hypertension".)

●

In patients who are overweight, measures to encourage weight loss should be instituted. (See "Overview of

therapy for obesity in adults".)

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cancer".)

While the issue of efficacy of vaccination with hepatitis B (HepB) vaccine has not been completely resolved, the

risks posed by HepB vaccine to patients with SLE must, at most, be very small [63,66].

Prophylaxis for Pneumocystis pneumonia is discussed elsewhere. (See "Treatment and prevention of

Pneumocystis pneumonia in non-HIV-infected patients", section on 'Systemic lupus erythematosus'.)

Radiation therapy — Anecdotal reports of increased toxicity following therapeutic ionizing radiation have made

radiation oncologists wary of treating patients with SLE and other collagen vascular disorders [67]. Patients with

scleroderma may be at greater risk. However, if needed, radiation therapy may be used in patients with SLE to treat

malignant disease.

Among the studies and reviews that have addressed the safety and toxicity of radiation therapy in patients with SLE

[49,68-71] the following are illustrative:

Patients who have an overlap of scleroderma with SLE appear to be at highest risk of marked fibrotic reaction to

radiation therapy.

Treating comorbid conditions — Accelerated atherosclerosis, pulmonary hypertension, and antiphospholipid

antibodies, 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 [6]:

Avoidance of specific medications — Some data suggest that sulfonamide-containing antibiotics (eg,

sulfadiazine, trimethoprim-sulfamethoxazole, sulfisoxazole) may cause exacerbations and should, therefore, be

avoided [72]. This impression with regard to sulfa-containing agents was supported by the following:

In 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

Two observational series have included 19 patients with SLE among those with “collagen vascular diseases”

receiving radiation therapy for cancer [68,69]. No unusually severe local reactions in the skin or subcutaneous

tissues in the radiation portal were noted in those with lupus.

●

One study included 17 patients with SLE who received radiation therapy [49]. Four patients had a grade 3 or

higher toxicity at 5 to 10 years. There was a trend toward greater toxicity with more severe disease and with

more extensive organ involvement.

●

Accelerated atherosclerosis (see "Coronary heart disease in systemic lupus erythematosus", section on

'Prevention and treatment')

●

Pulmonary hypertension – Although an imperfect screening test, Doppler echocardiography is usually used as

the initial noninvasive study for pulmonary hypertension. (See "Clinical features and diagnosis of pulmonary

hypertension in adults".)

●

Antiphospholipid antibodies – The presence of antiphospholipid antibodies is assessed by assays for

antibodies to cardiolipin (aCL), for antibodies to beta 2 glycoprotein-1 (anti-ß2 glycoprotein-I), and for the

presence of lupus anticoagulant (LA) activity. (See "Diagnosis of the antiphospholipid syndrome".)

●

Osteopenia or osteoporosis – Bone mineral density determination may detect the presence of osteopenia or

osteoporosis and may allow dietary or medical interventions to prevent or reverse bone demineralization. (See

"Screening for osteoporosis".)

●

A case-control study of 145 patients with SLE and 104 controls, in which adverse reactions to sulfonamide-

containing antibiotics were more than twice as frequent in those with SLE (52 versus 19 percent) [73]

●

A study of 417 patients with SLE, among whom 114 (27 percent) had a history of sulfonamide allergy [74]●

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the two disorders. (See "Drug-induced lupus".)

Minocycline can also cause drug-induced lupus. We advise against its use in patients with SLE. (See "Drug-

induced lupus", section on 'Overview of causative drugs' and "Drug-induced lupus".)

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. (See "Pregnancy

in women with systemic lupus erythematosus".)

Oral contraceptives containing high-dose estrogens can cause exacerbations of SLE. However, this complication

rarely occurs with the current use of low-dose estrogen or progesterone-containing compounds. Patients with

migraine headaches, Raynaud phenomenon, a history of phlebitis, or antiphospholipid antibodies probably should

not be treated with oral contraceptives. Hormone replacement therapy in postmenopausal women may be

associated with a modest increase in the rate of flares, and decisions about use of estrogen for postmenopausal

symptoms must be carefully considered weighing the potential benefits against risks of thrombotic events and of

breast and uterine cancer [75]. (See "Menstrual function, menopause, and hormonal contraceptives in women with

systemic lupus erythematosus".)

Pregnant patients with active lupus are generally managed with glucocorticoids. Other drugs used during pregnancy

include nonsteroidal antiinflammatory drugs (avoided during early pregnancy and in the third trimester) and

hydroxychloroquine (probably safe). Cyclophosphamide, cyclosporine, mycophenolate mofetil, and methotrexate

are contraindicated, while azathioprine can be cautiously used. (See "Pregnancy in women with systemic lupus

erythematosus" and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during

pregnancy and lactation".)

TREATMENT OF SPECIFIC ORGAN INVOLVEMENT — A number of medications are commonly used in the

treatment of systemic lupus erythematosus (SLE), including nonsteroidal antiinflammatory drugs (NSAIDs),

antimalarials (primarily hydroxychloroquine), glucocorticoids, and immunosuppressive agents (including

cyclophosphamide, cyclosporine, tacrolimus, leflunomide, methotrexate, azathioprine, mycophenolate, and

belimumab). Patient compliance with recommended treatment is, as expected, associated with better outcomes

than noncompliance [76].

What follows is a general overview of which drugs are preferred in selected clinical settings:

Topical therapies are often useful for cutaneous manifestations of lupus and reduce the risk of side effects that

are associated with systemic use of NSAIDs, glucocorticoids, or immunosuppressants.

●

NSAIDs are generally effective for musculoskeletal complaints, fever, headaches, and mild serositis.

Naproxen may have greater relative cardiovascular safety than other NSAIDs. Celecoxib has been used in

SLE patients, even in those with “sulfa” allergy, without precipitating any allergic response but should be

administered with caution [77]. (See "Musculoskeletal manifestations of systemic lupus erythematosus" and

"Overview of selective COX-2 inhibitors", section on 'Sulfonamide allergy'.)

●

Antimalarials are most useful for skin manifestations and for musculoskeletal complaints. In addition, in long-

term studies, the use of antimalarials, such as hydroxychloroquine, prevented major damage to the kidneys

and central nervous system [78,79]. Their use may also reduce the risk of disease flares, though this is less

clear for renal and central nervous system (CNS) manifestations [80]. Antimalarials and their use in SLE are

discussed in detail elsewhere. (See "Mucocutaneous manifestations of systemic lupus erythematosus" and

"Antimalarial drugs in the treatment of rheumatic disease".)

●

Systemic glucocorticoids (eg, high doses of 1 to 2 mg/kg/day of prednisone or equivalent or intermittent

intravenous “pulses” of methylprednisolone) used alone or in combination with immunosuppressive agents are

generally reserved for patients with significant organ involvement, particularly renal and CNS disease. There is

a paucity of data to support the use of intravenous “pulse” versus daily oral glucocorticoids [81]. Patients with

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OTHER THERAPIES — Several types of agents have been used in patients resistant to more well-established

therapeutic approaches, including biologic agents that target either B cells or T cells.

Patients with severe organ involvement who are resistant to cyclophosphamide therapy generally do poorly. The

optimal approach to such patients is uncertain. (See "Therapy of diffuse or focal proliferative lupus nephritis".)

Belimumab — Belimumab (Benlysta, formerly termed Lymphostat-B) is a fully human monoclonal antibody that

inhibits the biologic activity of the soluble form of a B-cell survival factor, B-lymphocyte stimulator or BLyS (also

known as B-cell activating factor belonging to the tumor necrosis factor [TNF] family [BAFF]); belimumab has

become available in the United States for the treatment of patients with active autoantibody-positive systemic lupus

organ-threatening disease (eg, cardiopulmonary, hepatic, renal, hemolytic anemia, immune

thrombocytopenia) are usually given the above-mentioned oral doses, whereas non-organ-threatening disease

(eg, cutaneous, musculoskeletal, constitutional) patients usually respond to 5 to 15 mg of prednisone (or

equivalent) daily until a glucocorticoid-sparing agent or antimalarial can take effect.

Immunosuppressive medications other than glucocorticoids (eg, methotrexate [82], cyclophosphamide,

azathioprine, mycophenolate, or rituximab) are generally reserved for patients with significant organ

involvement and/or for patients who have had an inadequate response to glucocorticoids. The use of

cyclophosphamide and other immunosuppressive agents in SLE is discussed in greater detail elsewhere.

(See "Therapy of diffuse or focal proliferative lupus nephritis" and "Clinical features and therapy of

membranous lupus nephritis" and "Therapy of resistant or relapsing diffuse or focal proliferative lupus

nephritis" and "Neurologic manifestations of systemic lupus erythematosus" and "Mucocutaneous

manifestations of systemic lupus erythematosus" and "Systemic lupus erythematosus in children: Pulmonary

manifestations" and "Gastrointestinal manifestations of systemic lupus erythematosus" and "Pulmonary

manifestations of systemic lupus erythematosus in adults" and "Management of refractory discoid lupus and

subacute cutaneous lupus" and "Hematologic manifestations of systemic lupus erythematosus in adults" and

"Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Neuropsychiatric

manifestations of systemic lupus erythematosus".)

Immunosuppressive agents such as mycophenolate, azathioprine, or cyclophosphamide are given with

glucocorticoids to patients with more than mild lupus nephritis, and cyclophosphamide is given to those with

alveolar hemorrhage, to those with systemic vasculitis, and to most patients with significant CNS involvement.

Lower doses of glucocorticoids (eg, ≤10 mg/day of prednisone) may be used for symptomatic relief of severe

arthralgia, arthritis, or serositis while awaiting a therapeutic effect from other medications. (See "Therapy of

diffuse or focal proliferative lupus nephritis" and "Neurologic manifestations of systemic lupus erythematosus"

and "Pulmonary manifestations of systemic lupus erythematosus in adults".)

●

Belimumab is available in the United States for the treatment of patients with active SLE who are receiving

standard therapy, such as NSAIDs, glucocorticoids, antimalarials, and/or immunosuppressives [83]. However,

it has not been adequately studied in patients with severe active lupus nephritis or with CNS lupus or in

patients who have previously used rituximab or who have recently used intravenous cyclophosphamide. The

role of belimumab in SLE treatment is uncertain. (See 'Belimumab' below.)

●

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA sulfate) are major circulating

androgens, and dietary supplements containing these androgenic steroids are widely available (see

"Dehydroepiandrosterone and its sulfate"). Women with systemic lupus erythematosus have low serum DHEA

and DHEA sulfate concentrations, even prior to initiating chronic glucocorticoid therapy [84]. A 2007 meta-

analysis concluded that DHEA probably leads to little or no important difference in disease activity in people

with mild to moderate SLE; it may improve overall well being but does so at the expense of androgenic side

effects including acne, hair growth, and menstrual changes [85]. In addition, because the purity and potency

of available dietary supplements are uncontrolled, use of DHEA or DHEA sulfate supplements is not

recommended.

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erythematosus (SLE) who are receiving standard therapy, including NSAIDs, glucocorticoids, antimalarials, or

immunosuppressives [83,86-90]. It has not been evaluated in patients with severe active lupus nephritis or with

severe active central nervous system lupus, nor has it been studied in combination with other biologics or

intravenous cyclophosphamide. Also, the use of belimumab is not recommended by the manufacturer in these

situations [91]. However, the role of belimumab in SLE treatment is evolving. (See "The humoral immune response",

section on 'TACI, BAFF and APRIL'.)

Based upon the available data and upon our clinical experience, we suggest limiting the use of belimumab to

patients who are similar to those enrolled in the two major trials, such as those with active musculoskeletal or

cutaneous disease. The dose regimen recommended by the manufacturer is 10 mg/kg at two-week intervals for the

first three doses and at four-week intervals thereafter.

We advise limiting its use to patients who require at least 10 mg daily of prednisone along with antimalarials and

with azathioprine, mycophenolate, or methotrexate to maintain control of disease activity or to patients who are

intolerant of such medications. We do not recommend its use for the purpose of treating severe active lupus

nephritis or severe active central nervous system (CNS) lupus until efficacy has been shown for these indications.

Live vaccines should not be given concurrently with belimumab.

Levels of BLyS are elevated in some patients with SLE, and it may play a role in the pathogenesis of lupus by

promoting the formation and survival of memory B cells and plasmablasts making autoantibodies. Inhibition of BLyS

can reduce the numbers of B cells and short-lived plasma cells and can decrease anti-double stranded DNA

antibody titers [86]. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Immune

abnormalities'.)

Two randomized, multinational trials (the BLISS-52 trial and BLISS-76 trial) involving a total of 1684 patients

demonstrated the efficacy and safety of belimumab [87,88]. In the BLISS-52 trial, 867 patients with active lupus and

with a positive antinuclear antibody (ANA) or anti-double-stranded DNA antibody were randomly assigned to receive

belimumab 10 mg/kg or 1 mg/kg (administered intravenously on days 0, 14, and 28 and every 28 days until 48

weeks) or placebo infusions, together with their standard care, including NSAIDs, antimalarials, glucocorticoids,

and immunosuppressives [87]. Outcomes were assessed with a novel endpoint, the SLE responder index (SRI),

which was developed based upon a retrospective analysis of data from an earlier randomized trial of belimumab

[92]. Patients were defined as responders based upon the following:

A significantly higher likelihood of achieving an SRI at one year was observed with belimumab (10 or 1 mg/kg)

compared with placebo (58 and 51 percent versus 44 percent, odds ratios (OR) 1.83, 95% CI 1.3-2.59, and 1.55,

95% CI 1.1-2.19, respectively). Additionally, belimumab was glucocorticoid-sparing. Those with a baseline dose of

prednisone greater than 7.5 mg/day who received belimumab were significantly more likely, compared with patients

receiving placebo, to experience a sustained reduction in glucocorticoid doses (28 and 24 percent versus 15

percent, OR 1.96, 95% CI 1.25-3.07, and 1.6, 95% CI 1.01-2.53, respectively).

Similar but more modest benefit was described at 52 weeks in a preliminary report of the other large randomized

trial (BLISS-76), although, at 76 weeks, the degree of benefit was no longer statistically significant [88,89].

The overall adverse event rates were similar in the patients receiving belimumab (10 or 1 mg/kg) or placebo in the

Overall improvement in disease activity of at least four points on the SLE Disease Activity Index (SLEDAI) as

modified for the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) trial (the

SELENA-SLEDAI) [46]

●

A lack of significant disease progression in any single dimension or organ system, as indicated by the

absence of a new British Isles Lupus Assessment Group (BILAG) A organ domain score and by no more than

one new BILAG B organ domain score [93,94]

●

No worsening (less than a 0.3 out of 3 increase) in the Physician’s Global Assessment (PGA) compared with

baseline [46]

●

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published BLISS-52 trial, including serious infections, which were seen in 4 to 8 percent of patients. However, the

FDA reported that, during all clinical studies and trials of the drug, more deaths and serious infections occurred with

belimumab compared with placebo [83]. Severe or serious hypersensitivity reactions were seen on infusion days in

two patients in each belimumab group (less than 1 percent) but in none of the patients receiving placebo in the

BLISS-52 trial. The most common adverse reactions in the clinical trials (occurring in at least 5 percent of patients)

were nausea, diarrhea, and fever. Nasopharyngitis, bronchitis, insomnia, pain in the extremities, depression,

migraine, and pharyngitis were also commonly reported.

Post hoc analyses have further examined the results of these trials [95-98]. Reported benefits include less active

disease, improved laboratory parameters, decreased musculoskeletal and mucocutaneous involvement,

improvements in health quality of life outcomes, and decreased requirements for glucocorticoids.

There are several limitations to the available data regarding the benefits of belimumab in SLE:

Thus, further studies are required to define the clinical utility of belimumab.

Rituximab — Monoclonal anti-B lymphocyte antibodies may be beneficial for patients with disease that is

resistant to other therapy [99]. However, concern has arisen from case reports of a possible association of the use

of the chimeric anti-CD20 monoclonal antibody agent, rituximab, with fatal progressive multifocal

leukoencephalopathy (PML) due to reactivation of latent infection with the JC virus; such reports in two patients with

SLE caused the United States Food and Drug Administration (FDA) to issue an alert to health providers [100,101].

Both patients had received other immunosuppressive therapies. Other case reports of PML in patients treated for

other diseases with rituximab [101-105] suggest that B-cell depleting therapies should be used cautiously. (See

"Clinical manifestations and diagnosis of JC, BK, and other polyomavirus infections" and "Progressive multifocal

leukoencephalopathy: Prognosis and treatment".)

Rituximab, cyclophosphamide, and glucocorticoids — The combination of the B-cell depleting chimeric

monoclonal antibody rituximab, cyclophosphamide, and high-dose glucocorticoids, as used in the treatment of

lymphoma, has shown some promise in uncontrolled, observational studies [106-109]. The potential benefits and

adverse effects were illustrated in a large study of this combination in 90 patients with SLE refractory to

conventional treatment [107]. Following rituximab infusion, patients were followed for 3 to 40 months. A “meaningful”

decrease in disease activity was noted in 80 percent, and infusions were well-tolerated in 90 percent of patients.

However, adverse events (ascribed to hypersensitivity to the chimeric antibody) occurred in 10 percent.

Rituximab without cyclophosphamide — Despite promising reports from uncontrolled studies [110-113], a

placebo-controlled, randomized trial of 257 patients with active SLE (EXPLORER trial), which excluded those with

nephritis, noted no significant difference in outcomes between those who received prednisone plus two infusions of

rituximab and those who received prednisone plus placebo infusions [114].

Improvement in lupus nephritis following rituximab treatment was noted in a series of 10 patients; five achieved a

complete remission a median of three months after beginning rituximab treatment [115]. Eight patients experienced

partial remissions at a median of two months. However, a large randomized study with a similar design to

EXPLORER of rituximab in patients with lupus nephritis (LUNAR trial) was not successful [116]. This may have

The subset of patients of African heritage and of African-Americans in the two major trials did not respond to

treatment with belimumab, although insufficient numbers of such patients were enrolled to draw definite

conclusions; additional studies in this population will be performed [83].

●

Patients who had received prior B-cell targeted therapy, such as rituximab, or who had received intravenous

cyclophosphamide within the preceding six months were excluded from the trials.

●

Belimumab has not been compared with any other active therapeutic agent used in the treatment of SLE, nor

has it been studied in combination with other biologic agents or with cyclophosphamide.

●

Patients with severe active lupus nephritis or severe active CNS lupus were excluded from the trials.●

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been due to patients in both study arms having been given highly effective therapy with large doses of

glucocorticoids and immunosuppressive agents, and the open label extension part of the protocol was halted due to

concern relating to PML.

Hematopoietic stem cell transplantation — The proposed mechanism of action of hematopoietic stem cell

transplantation is that it provides a period free from memory T-cell influence, during which maturation of new

lymphocyte progenitors can occur without recruitment to anti-self activity. (See "The adaptive cellular immune

response", section on 'Memory T cells'.)

Results from this approach are limited and include:

Autologous stem cell transplantation remains complex, costly, and, despite improvements in treatment-related

mortality, risky. Additional study, including direct comparison with more conventional treatment approaches in

randomized controlled trials, is needed before any recommendation can be made regarding the role of stem cell

transplantation in the treatment of SLE. Use of allogenic stem cells is an interesting alternative for which there are

insufficient data to assess efficacy or safety.

Immunoablation alone — Immunoablation without bone marrow or stem cell support has also been effective in

some patients with moderate to severe SLE refractory to glucocorticoids and immunosuppressive therapy [119].

However, safety concerns caused the US National Institutes of Health to halt their trial that was examining the

effectiveness of immunoablation alone.

Cyclosporine — Cyclosporine (or ciclosporin) inhibits the transcription process that is normally associated with T-

cell activation (see "Pharmacology and side effects of cyclosporine and tacrolimus", section on 'Mechanism of

action'). Addition of cyclosporine may allow a reduction in the use of glucocorticoids. As an example, an unblinded

study randomly assigned 89 patients with SLE, who were taking ≥15 mg of prednisolone per day and who required

the addition or change of a glucocorticoid-sparing drug, to receive either cyclosporine or azathioprine [120].

Both cyclosporine and azathioprine allowed reduction in prednisolone dose at the end of one year of study. There

was no statistically significant difference between cyclosporine and azathioprine in the reduction in dose (mean

decrease in daily prednisolone dose of 9 mg and 10.7 mg, respectively, a difference of -1.7 mg [95% CI -4.4 to

+0.9]).

Similar rates of study drug discontinuation were noted for each group. Discontinuations due to lack of efficacy and

due to side effects were also similar. In this study, neither severe hypertension nor irreversible renal injury occurred

in the cyclosporine-treated subjects. However, hypertension was noted more frequently in patients who received

cyclosporine (49 versus 14 percent), as was an increase in the serum creatinine (13 versus 2 percent). When

cyclosporine is used in clinical practice, these side effects must be anticipated. Frequent monitoring of blood

pressure and renal function is necessary for appropriate dose titration. (See "Cyclosporine and tacrolimus

nephrotoxicity".)

Other agents in clinical trials — A number of other therapeutic approaches have been tried or are under

investigation in SLE, some of which are available for use in other immune-mediated conditions including rheumatoid

arthritis. These include intravenous immunoglobulin; thalidomide; zileuton; sirolimus; eculizimab; anti-interleukin

High-dose chemotherapy followed by autologous stem cell transplantation administered to 50 patients with

glomerulonephritis, cerebritis, transverse myelitis, autoimmune cytopenia, catastrophic antiphospholipid

syndrome, and/or vasculitis despite intravenous cyclophosphamide [117]. The overall five-year survival was 84

percent, and the probability of disease survival at five years was 50 percent. Treatment related mortality, in an

intention to treat analysis, was 4 percent.

●

Results from the European Registry of autologous stem cell transplantation for SLE, which were notable for

induction of remission of disease activity in 33 of 50 cases [118]. However, one-third of the patients relapsed

at a median of six months. Survival was 62 percent at 48 months, with a treatment-related mortality of 12

percent.

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(IL)-10; B-cell targeted therapy including epratuzumab, tabalumab, atacicept; blisibimod; tolerogens such as

lupuzor and laquinimod; bortezomib; anti-Jak/stat or tyrosine kinases; mizoribine; immunoadsorption, via perfusion

of patients’ blood through a column of immobilized C1q or polyclonal sheep anti-human immunoglobulin;

recombinant monoclonal antibody that inhibits ligand binding to the human interleukin-6 receptor (tocilizumab);

sirukumab; interleukin-21 antagonist; spliceosomal peptide P140; non-coding (micro)RNA molecules; interferon-

alpha and -gamma inhibitors such as sifalimumab, rontalizumab, AGS 009, and fontolizumab; an anti-TNF

monoclonal antibody (infliximab); AMG-557; and a T-cell costimulation blocker (abatacept) [47,48,120-137].

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. Most patients have a

relapsing and remitting course, which may be associated with the use of high-dose glucocorticoids during the

treatment of severe flares.

Patient survival — The five-year survival rate in SLE has dramatically increased since the mid-20th century from

approximately 40 percent in the 1950s to more than 90 percent in studies beginning after 1980 [138-140], a trend

that has continued into the early 21st century [141].

The likelihood of survival can be ranked on the basis of organ involvement (skin and musculoskeletal are best,

central nervous system and kidney are worst) and on the number of American College of Rheumatology criteria for

SLE (table 2) [142]. Older age, male sex, poverty, and a low complement may also be poor prognostic factors, as

was noted in a cohort of North American patients [140]. However, increasing age was not a predictor of an

increased mortality rate in one Chinese cohort of 442 patients when compared with an age-adjusted population

mortality rate [143]. Measures of disease activity and accumulated organ damage may also be predictive of

increased mortality while use of antimalarial drugs may reduce mortality rates [141].

The improvement in patient survival is probably due to multiple factors. These include increased disease recognition

with more sensitive diagnostic tests [144], earlier diagnosis or treatment, the inclusion of milder cases, increasingly

judicious therapy, and prompt treatment of complications [145].

In a 2002 report from the Centers for Disease Control in the United States, deaths due to SLE varied among

different population groups [146]. As examples, the proportion of deaths due to SLE was more than five times

higher in women than men and was more than three times higher in black compared with white women. More than

one-third of deaths due to lupus occurred in people aged 15 to 44 years.

Causes of death — The major cause of death in the first few years of illness is active disease (eg, central

nervous system [CNS], renal, or cardiovascular disease) or infection due to immunosuppression, while late deaths

are caused by the illness (eg, end-stage renal disease), by treatment complications (including infection and

coronary disease), by non-Hodgkin lymphoma, and by lung cancer [145,147-151].

The frequency of the different causes of death can be illustrated by the following observations:

The largest study included survival data and causes of death in a total of 9547 patients who were followed for

an average of 8.1 years [151]. Standardized mortality rates (SMR) of SLE patients to expected rates for an

age- and sex-adjusted population were noted for circulatory disease (SMR 1.7), especially heart disease

(SMR 1.7); for non-Hodgkin lymphoma (SMR 2.8); for lung cancer (SMR 19.4); for infections (SMR 9.0),

especially pneumonia (SMR 7.2); and for renal disease (SMR 4.3). Those at particularly high risk for mortality

were younger, female, and black, with disease duration of less than one year.

●

One study evaluated the causes of death in 408 patients with SLE followed over a mean period of 11 years;

144 (35 percent) died [152]. The major causes of death were active lupus (34 percent), infection (22 percent),

cardiovascular disease (16 percent), and cancer (6 percent). Deaths that resulted directly from SLE and

infection were common among younger patients; the risk of death directly due to SLE was highest in the first

three years after diagnosis.

●

Another prospective study followed 1000 patients for 10 years [139]. The most frequent causes of death were●

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Serious infection is most often due to immunosuppressive therapy (see "Secondary immune deficiency induced by

drugs and biologics"). Patients at particular risk are those treated with both glucocorticoids and cyclophosphamide,

especially if the white blood cell count is less than 3000/microL and/or if high-dose glucocorticoids are given

[155,156]. Lymphopenia (<1000/microL) at presentation may be an independent risk factor [157]. (See "General

toxicity of cyclophosphamide and chlorambucil in inflammatory diseases" and "Major side effects of systemic

glucocorticoids".)

Premature coronary artery disease is being increasingly recognized as a cause of late mortality. (See "Coronary

heart disease in systemic lupus erythematosus".)

Is cancer risk increased? — Although the relation of SLE to malignancy was previously unclear because

conflicting data [151,158-163], a clear increase of certain malignancies in patients with SLE was subsequently

recognized.

Antimalarial drug use may be associated with a reduced risk of cancer. This is suggested by the results of an

observational study of 235 Spanish patients, among whom two-thirds were treated at some time with an antimalarial

drug while one-third were never treated with one of these agents [171]. After adjustment for other risk factors, use of

antimalarial drugs was associated with a statistically significant (85 percent) reduction in the relative risk of

malignant disease. Further study of the influence of antimalarial drug use on the incidence of cancer did not confirm

these initial results [167]. These agents are used to treat some specific types of organ involvement. (See 'Treatment

of specific organ involvement' above.)

Although some data suggest that the use of immunosuppressive drugs may be associated with the later

development of hematologic malignancies [172], there is insufficient information to conclude whether or not the use

of immunosuppressive medications in patients with SLE increases their risk for malignancies [167].

active SLE (26 percent), infection (25 percent), and thromboses (26 percent) [139].

A cohort of 694 SLE patients were followed longitudinally for 10 years, and the effect of renal disease,

histologic class of lupus nephritis, renal damage and renal failure on the SMR and life expectancy were

reported. The life expectancy of SLE patients with renal disease and those with renal damage was reduced

by 15 years and 24 years, respectively, compared to the general population [153].

●

In a cohort of 4747 Swedish patients who were diagnosed with SLE between 1964 and 1995, the proportions

of deaths due to cardiovascular events, SLE, and malignant disease were 42 percent, 21 percent, and 12

percent, respectively [154].

●

An increased risk in patients with SLE, predominantly for that of non-Hodgkin type lymphoma, which was

found in a 2005 meta-analysis [164]. Non-Hodgkin lymphoma in patients with SLE is often an aggressive

histologic subtype, especially diffuse large B-cell lymphoma [165,166].

●

An association with Hodgkin lymphoma [167]●

An increase in lung cancer [167]. Smoking was a predictor for lung cancer in women with SLE.●

A twofold increase in the incidence of breast cancer when compared with an age- and gender-matched

segment of the population (standardized incidence ratio of 2.1) [168]

●

An increase of squamous skin cancer among 238 patients with SLE in Iceland [169]●

An increased frequency of abnormal cervical Papanicolaou (Pap) smears in women with SLE [170]. The risk

factors for the development of an abnormal Pap smear include a history of sexually transmitted diseases, the

use of oral contraceptives, and the use of immunosuppressive drugs.

●

An increased incidence of cervical cancer in one study [162]●

An increased risk of vaginal or vulvar cancer, which was seen in one study (RR 5.7) [158]●

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Prognostic factors — Poor prognostic factors for survival in SLE include [139,142,149,152,158,173-179]:

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

[180]. 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 [181]. (See "Major side effects of systemic glucocorticoids"

and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Factors that may be associated with a shorter delay between disease onset and organ damage include [182]:

Glucocorticoid use at doses equivalent to prednisone ≥10 mg/day was 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 SLE patients 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 [183].

Clinical remission — After appropriate therapy, some patients go into a clinical remission, requiring no treatment

[184,185]. The frequency with which this occurs was addressed in two long-term follow-up studies.

In one study of 667 patients, the following were noted [184]:

In a second study of 703 patients, 46 achieved complete clinical remission of at least one-year duration [186].

However, of these, only 12 were still in remission after five years.

These observations demonstrate that remission is uncommon, and, even when achieved, it is frequently not

sustained.

Renal disease (especially diffuse proliferative glomerulonephritis)●

Hypertension●

Male sex●

Young age●

Older age at presentation●

Poor socioeconomic status●

Black race, which may primarily reflect low socioeconomic status●

Presence of antiphospholipid antibodies●

Antiphospholipid syndrome●

High overall disease activity (eg, hemolytic anemia, thrombotic thrombocytopenic purpura [TTP], alveolar

hemorrhage, pulmonary hypertension, mesenteric vasculitis)

●

Hispanic ethnicity●

Greater disease activity●

A history of thrombotic events●

Glucocorticoid use of less than 10 mg per day●

Approximately 25 percent had at least one treatment-free clinical remission lasting for at least one year. The

mean duration of remission was 4.6 years, which represents an underestimate since one-half of the patients

were still in remission at the end of follow-up.

●

A long history of SLE or the presence of renal or neuropsychiatric disease did not preclude remission.●

Among the 48 percent of patients who relapsed after achieving remission, one-half did not achieve a

subsequent remission.

●

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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 to 6 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 to 12 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.)

SUMMARY AND RECOMMENDATIONS

th th

th th

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

Beyond the Basics topics (see "Patient information: Systemic lupus erythematosus (SLE) (Beyond the

Basics)" and "Patient information: Systemic lupus erythematosus and pregnancy (Beyond the Basics)")

●

An effective therapeutic regimen for the treatment of systemic lupus erythematosus (SLE) first requires the

accurate determination of both disease activity and severity. Disease activity usually refers to the degree of

inflammation, while the degree of severity depends upon the level of organ dysfunction and upon the organ’s

relative importance. The degree of irreversible organ disfunction has been referred to as the “damage index.”

Disease activity is assessed using a combination of the clinical history, physical examination, organ-specific

functional tests, and serologic studies. The frequency with which monitoring laboratory tests are performed is

tailored to each patient, generally depending upon the level of disease activity. (See 'Determination of disease

activity and severity' above and 'Clinically useful markers of activity' above and 'Frequency of laboratory testing'

above.)

●

The pattern and severity of organ involvement determines specific drug therapy, but a number of general

issues are applicable to every patient with SLE. Adherence to medication regimens, maintenance of good

sleep hygiene, and follow-through with recommended testing are of particular importance. Patients should

also be informed of the availability of resource information relating to the treating center and to lupus patient

support organizations. Other important issues include protection from sunlight and from other sources of

ultraviolet light; a balanced approach to diet and nutrition, considering clinical needs; exercise; smoking

cessation; immunizations; treatment of comorbid conditions; avoidance of certain medications; and avoidance

of pregnancy during active disease. (See 'General treatment considerations' above.)

●

A number of medications are commonly used in the treatment of SLE, including nonsteroidal antiinflammatory

drugs (NSAIDs), antimalarials (primarily hydroxychloroquine), glucocorticoids, and agents that are

immunosuppressive or immunomodulatory (including cyclophosphamide, cyclosporine, tacrolimus,

leflunomide, methotrexate, azathioprine, mycophenolate, and belimumab). Certain drugs are preferred in

selected clinical settings. (See 'Treatment of specific organ involvement' above and 'Other therapies' above.)

●

Patients with severe organ involvement who are resistant to cyclophosphamide therapy generally do poorly.

The optimal approach to such patients is uncertain. A number of investigational strategies are under

investigation. (See 'Other therapies' above.)

●

SLE can run a varied clinical course, ranging from a relatively benign illness to a rapidly progressive disease

with fulminant organ failure and death. Most patients have a relapsing and remitting course, which may be

associated with the use of high-dose glucocorticoids during the treatment of severe flares. The five-year

survival rate has improved to greater than 90 percent due to multiple factors. The major cause of death in the

first few years of illness is active disease or infection due to immunosuppression, while causes of late deaths

include the illness, treatment complications, non-Hodgkin lymphoma, and lung cancer. There is an increase in

●

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Topic 4675 Version 22.0

the frequency of certain malignancies in patients with SLE. (See 'Prognosis' above and 'Patient survival'

above.)

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. After

appropriate therapy, some patients go into a clinical remission, requiring no treatment. However, remission is

uncommon, and, even when achieved, it is frequently not sustained. (See 'Morbidity' above and 'Clinical

remission' above.)

●

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GRAPHICS

Classification criteria for systemic lupus erythematosus

ACR criteria for the classification of

systemic lupus erythematosus

SLICC criteria for the classification

of systemic lupus erythematosus

(4 of 11 criteria)* (4 of 17 criteria, including at least one clinical

criterion and one immunologic criterion; OR

biopsy-proven lupus nephritis )

Criterion Definition Criterion Definition

Clinical criteria

Malar rash Fixed erythema, flat or

raised, over the malar

eminences, tending to

spare the nasolabial

folds

Acute cutaneous

lupus

Lupus malar rash (do

not count if malar

discoid); bullous lupus;

toxic epidermal

necrolysis variant of

SLE; maculopapular

lupus rash;

photosensitive lupus

rash (in the absence of

dermatomyositis); OR

subacute cutaneous

lupus (nonindurated

psoriaform and/or

annular polycyclic lesions

that resolve without

scarring, although

occasionally with

postinflammatory

dyspigmentation or

telangiectasias)

Photosensitivity Skin rash as a result of

unusual reaction to

sunlight, by patient

history or clinician

observation

Discoid rash Erythematosus raised

patches with adherent

keratotic scaling and

follicular plugging;

atrophic scarring may

occur in older lesions

Chronic

cutaneous lupus

Classic discoid rash;

localized (above the

neck); generalized

(above and below the

neck); hypertrophic

(verrucous) lupus; lupus

panniculitis (profundus);

mucosal lupus; lupus

erythematosus tumidus;

chilblains lupus; OR

discoid lupus/lichen

planus overlap

Nonscarring Diffuse thinning or hair

[1,2] [3]

•

Δ

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alopecia fragility with visible

broken hairs (in the

absence of other

causes, such as alopecia

areata, drugs, iron

deficiency, and

androgenic alopecia)

Oral ulcers Oral or nasopharyngeal

ulceration, usually

painless, observed by a

physician

Oral or nasal

ulcers

Palate, buccal, tongue,

OR nasal ulcers (in the

absence of other

causes, such as

vasculitis, Behçet's

disease, infection

(herpesvirus),

inflammatory bowel

disease, reactive

arthritis, and acidic

foods)

Arthritis Nonerosive arthritis

involving two or more

peripheral joints,

characterized by

tenderness, swelling, or

effusion

Joint disease Synovitis involving two

or more joints,

characterized by

swelling or effusion OR

Tenderness in two or

more joints and at least

30 minutes of morning

stiffness

Serositis Pleuritis - convincing

history of pleuritic pain

or rubbing heard by

a clinician or evidence of

pleural effusion OR

Serositis Typical pleurisy for more

than one day, pleural

effusions, or pleural rub,

OR

Pericarditis -

documented by EKG,

rub, or evidence of

pericardial effusion

Typical pericardial pain

(pain with recumbency

improved by sitting

forward) for more

than one day, pericardial

effusion, pericardial rub,

or pericarditis by

electrocardiography in

the absence of other

causes, such as

infection, uremia, and

Dressler's syndrome

Renal disorder Persistent proteinuria

greater than 500 mg/24

hours or greater than 3+

if quantitation not

Renal Urine protein-to-

creatinine ratio (or 24-

hour urine protein)

representing 500 mg

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performed OR protein/24 hours, OR

Cellular casts - may be

red cell, hemoglobin,

granular, tubular, or

mixed

Red blood cell casts

Neurologic

disorder

Seizures OR psychosis -

in the absence of

offending drugs or

known metabolic

derangements (uremia,

ketoacidosis, or

electrolyte imbalance)

Neurologic Seizures; psychosis;

mononeuritis multiplex

(in the absence of other

known causes, such as

primary vasculitis);

myelitis; peripheral or

cranial neuropathy (in

the absence of other

known causes, such as

primary vasculitis,

infection, and diabetes

mellitus); OR acute

confusional state (in the

absence of other

causes, including

toxic/metabolic, uremia,

drugs)

Hematologic

disorder

Hemolytic anemia - with

reticulocytosis OR

Leukopenia - less than

4000/mm total on two

or more occasions OR

Lymphopenia - less than

1500/mm on two or

more occasions OR

Thrombocytopenia - less

than 100,000/mm (in

the absence of offending

drugs)

Hemolytic anemia Hemolytic anemia

Leukopenia or

lymphopenia

Leukopenia

(<4000/mm at least

once) (in the absence of

other known causes,

such as Felty's

syndrome, drugs, and

portal hypertension), OR

Lymphopenia

(<1000/mm at least

once) (in the absence of

other known causes,

such as glucocorticoids,

drugs, and infection)

Thrombocytopenia Thrombocytopenia

(<100,000/mm ) at

least once in the

absence of other known

causes, such as drugs,

portal hypertension, and

thrombotic

thrombocytopenic

purpura

3

3

3

3

3

3

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Immunologic criteria

ANA An abnormal titer of

antinuclear antibody by

immunofluorescence or

an equivalent assay at

any point in time and in

the absence of drugs

known to be associated

with "drug-induced

lupus" syndrome

ANA ANA level above

laboratory reference

range

Immunologic

disorders

Anti-DNA - antibody to

native DNA in abnormal

titer OR

Anti-Sm - presence of

antibody to Sm nuclear

antigen OR

Positive finding of

antiphospholipid

antibody based on an

abnormal serum level of

IgG or IgM anticardiolipin

antibodies, on a positive

test result for lupus

anticoagulant using a

standard method, or on

a false positive serologic

test for syphilis known

to be positive for at

least six months and

confirmed by Treponema

pallidum immobilization

or fluorescent

treponemal antibody

absorption test

Anti-dsDNA Anti-dsDNA antibody

level above laboratory

reference range (or

>twofold the reference

range if tested by ELISA)

Anti-Sm Presence of antibody to

Sm nuclear antigen

Antiphospholipid Antiphospholipid

antibody positivity as

determined by any of

the following: positive

test result for lupus

anticoagulant; false-

positive test result for

rapid plasma reagin;

medium- or high-titer

anticardiolipin antibody

level (IgA, IgG, or IgM);

or positive test result for

anti-beta 2-glycoprotein

I (IgA, IgG, or IgM)

Low complement Low C3; low C4; OR low

CH50

Direct Coombs'

test

Direct Coombs' test in

the absence of hemolytic

anemia

ACR: American College of Rheumatology; SLICC: Systemic Lupus International Collaborating Clinics;

SLE: systemic lupus erythematosus; EKG: electrocardiogram; ANA: antinuclear antibodies; anti-

dsDNA: anti-double-stranded DNA; ELISA: enzyme-linked immunosorbent assay; Anti-Sm: anti-

Smith antibody; IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M.

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* For the ACR criteria, no distinction is made between clinical and immunologic criteria in

determining whether the required number has been met. The classification is based upon 11

criteria. For the purpose of identifying patients in clinical studies, a person is said to have systemic

lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously,

during any interval of observation.

• For the SLICC criteria, criteria are cumulative and need not be presently concurrently. A patient is

classified as having SLE if he or she satisfies four of the clinical and immunologic criteria used in the

SLICC classification criteria, including at least one clinical criterion and one immunologic criterion.

Δ Alternatively, according to the SLICC criteria, a patient is classified as having SLE if he or she has

biopsy-proven nephritis compatible with SLE in the presence of ANAs or anti-dsDNA antibodies.

References:

1. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic

lupus erythematosus. Arthritis Rheum 1982; 25:1271.

2. Hochberg MC. Updating the American College of Rheumatology revised criteria for the

classification of systemic lupus erythematosus (letter). Arthritis Rheum 1997; 40:1725.

3. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International

Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum

2012; 64:2677.

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ACR criteria for the classification of systemic lupus erythematosus

Criterion Definition

Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare

the nasolabial folds

Discoid rash Erythematosus raised patches with adherent keratotic scaling and follicular

plugging; atrophic scarring may occur in older lesions

Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history

or clinician observation

Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a clinician

Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized

by tenderness, swelling, or effusion

Serositis Pleuritis - Convincing history of pleuritic pain or rub heard by a clinician or

evidence of pleural effusion OR

Pericarditis - Documented by EKG, rub, or evidence of pericardial effusion

Renal disorder Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if

quantitation not performed OR

Cellular casts - May be red cell, hemoglobin, granular, tubular, or mixed

Neurologic

disorder

Seizures OR psychosis - In the absence of offending drugs or known

metabolic derangements (uremia, ketoacidosis, or electrolyte imbalance)

Hematologic

disorder

Hemolytic anemia - With reticulocytosis OR

Leukopenia - Less than 4000/mm total on two or more occasions OR

Lymphopenia - Less than 1500/mm on two or more occasions OR

Thrombocytopenia - Less than 100,000/mm in the absence of offending

drugs

Immunologic

disorders

Anti-DNA - Antibody to native DNA in abnormal titer OR

Anti-Sm - Presence of antibody to Sm nuclear antigen OR

Positive antiphospholipid antibody on:

1. An abnormal serum level of IgG or IgM anticardiolipin antibodies, or

2. A positive test result for lupus anticoagulant using a standard method,

or

3. A false-positive test result for at least six months confirmed by

Treponema pallidum immobilization or fluorescent treponemal antibody

absorption test

Antinuclear

antibody

An abnormal titer of antinuclear antibody by immunofluorescence or an

equivalent assay at any point in time and in the absence of drugs known to

be associated with "drug-induced lupus" syndrome

ACR: American College of Rheumatology; EKG: electrocardiogram; IgG: immunoglobulin G; IgM:

immunoglobulin M.

3

3

3

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