Systemic Lupus Erythematosus

2739CHAPTER 356

when such responses are abnormal or prolonged, autoimmune disease

is favored.

Female sex is permissive for SLE with evidence for hormone effects,

genes on the X chromosome, and epigenetic differences between genders playing a role. Females of many mammalian species make higher

antibody responses than males. Women exposed to estrogen-containing

oral contraceptives or hormone replacement have an increased risk

of developing SLE (HR 1.2–2). Estradiol binds to receptors on T and

B lymphocytes, increasing activation and survival of those cells, especially autoreactive subsets, thus favoring prolonged immune responses.

Genes on the X chromosome that influence SLE, such as TREX1, may

play a role in gender predisposition, possibly because some genes on

the second X in females are not silent. People with XXY karyotype

(Klinefelter’s syndrome) have a significantly increased risk for SLE.

Several environmental stimuli may influence SLE (Fig. 356-1).

Exposure to ultraviolet light causes flares of SLE in ~70% of patients,

possibly by increasing apoptosis in skin cells or by altering DNA and

intracellular proteins to make them antigenic. Some infections and

lupus-inducing drugs activate autoreactive T and B cells; if such cells

are not appropriately regulated, prolonged autoantibody production

occurs. Most SLE patients have autoantibodies for 3 years or more

before the first symptoms of disease, suggesting that regulation controls the degree of autoimmunity for years before quantities and qualities of autoantibodies, activated innate immunity, pathogenic B and T

cells, and activated tissue-fixed cells cause clinical disease. Epstein-Barr

virus (EBV) may be one infectious agent that can trigger SLE in susceptible individuals. Children and adults with SLE are more likely to be

infected by EBV than age-, sex-, and ethnicity-matched controls. EBV

contains amino acid sequences that mimic sequences on human spliceosomes (RNA/protein antigens) often recognized by autoantibodies

in people with SLE. Current tobacco smoking increases risk for SLE

(HR 1.5). Prolonged occupational exposure to crystalline silica (e.g.,

inhalation of soap powder dust or soil in farming activities) increases

risk (HR 4.3) in African-American women. Exposure to pesticides

during childhood, both in residential use and in farming, increases the

risk of SLE. Long-term exposure to air pollution also increases the risk

of SLE. Thus, interplay between genetic susceptibility, environment,

gender, race, and abnormal immune responses results in autoimmunity

(Chap. 355).

■ PATHOLOGY

In SLE, biopsies of affected skin show deposition of Ig at the dermalepidermal junction (DEJ), injury to basal keratinocytes, and inflammation dominated by T lymphocytes in the DEJ and around blood vessels

and dermal appendages. Clinically unaffected skin may also show Ig

deposition at the DEJ. Lupus skin lesions are characterized by expression of IFN-regulated cytokines and chemokines and by IFN-producing pDCs and keratinocytes. These patterns are not specific for

dermatologic SLE; however, they are highly suggestive.

In renal biopsies, the pattern and severity of injury are important in

diagnosis and in selecting the best therapy. Most recent clinical studies of

lupus nephritis have used the International Society of Nephrology (ISN)

and the Renal Pathology Society (RPS) classification (Table 356-2). In

the ISN/RPS classification, the addition of “A” for active and “C” for

chronic changes gives physicians information regarding the potential

reversibility of disease. The system focuses on glomerular disease,

although the presence of tubular interstitial and vascular disease, as

well as the chronicity score in both glomeruli and interstitium, is

important in predicting clinical outcomes. In general, class III and IV

disease, as well as class V accompanied by III or IV disease, should be

treated with aggressive immunosuppression if possible because there is

a high risk for ESRD if patients are untreated or undertreated. In contrast, treatment for lupus nephritis is not recommended in patients with

class I or II disease or with extensive irreversible changes (class VI). In

the 2019 European League of Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for classification of SLE, a diagnosis

can be established on the basis of class III or class IV renal histology in

the presence of antinuclear autoantibodies, without meeting additional

criteria (Tables 356-3 and 356-4).

Histologic abnormalities in blood vessels may also determine therapy. Patterns of vasculitis are not specific for SLE but may indicate

active disease: leukocytoclastic vasculitis is most common (Chap. 363).

Lymph node biopsies are usually performed to rule out infection or malignancies. In SLE, they show nonspecific diffuse chronic

inflammation.

■ DIAGNOSIS

The diagnosis of SLE is based on characteristic clinical features and

autoantibodies. Two classification systems are currently in use: the

2012 Systemic Lupus International Collaborating Clinics (SLICC)

criteria and the 2019 EULAR/ACR classification in which clinical

manifestations are weighted. Both are shown in Tables 356-3 and 356-4.

The SLICC criteria are easier for evaluating an individual patient,

but the EULAR/ACR are more current and will probably be used for

TABLE 356-2 Classification of Lupus Nephritis (International Society

of Nephrology and Renal Pathology Society)

Class I: Minimal Mesangial Lupus Nephritis

Normal glomeruli by light microscopy, but mesangial immune deposits by

immunofluorescence.

Class II: Mesangial Proliferative Lupus Nephritis

Purely mesangial hypercellularity of any degree or mesangial matrix expansion

by light microscopy, with mesangial immune deposits. A few isolated

subepithelial or subendothelial deposits may be visible by immunofluorescence

or electron microscopy, but not by light microscopy.

Class III: Focal Lupus Nephritis

Active or inactive focal, segmental or global endo- or extracapillary

glomerulonephritis involving ≤50% of all glomeruli, typically with focal

subendothelial immune deposits, with or without mesangial alterations.

Class III (A): Active lesions—focal proliferative lupus nephritis

 Class III (A/C): Active and chronic lesions—focal proliferative and sclerosing

lupus nephritis

 Class III (C): Chronic inactive lesions with glomerular scars—focal sclerosing

lupus nephritis

Class IV: Diffuse Lupus Nephritis

Active or inactive diffuse, segmental or global endo- or extracapillary

glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse

subendothelial immune deposits, with or without mesangial alterations. This

class is divided into diffuse segmental (IV-S) lupus nephritis when ≥50% of

the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus

nephritis when ≥50% of the involved glomeruli have global lesions. Segmental is

defined as a glomerular lesion that involves less than one-half of the glomerular

tuft. This class includes cases with diffuse wire loop deposits but with little or no

glomerular proliferation.

Class IV-S (A): Active lesions—diffuse segmental proliferative lupus nephritis

Class IV-G (A): Active lesions—diffuse global proliferative lupus nephritis

 Class IV-S (A/C): Active and chronic lesions—diffuse segmental proliferative

and sclerosing lupus nephritis

 Class IV-G (A/C): Active and chronic lesions—diffuse global proliferative and

sclerosing lupus nephritis

 Class IV-S (C): Chronic inactive lesions with scars—diffuse segmental

sclerosing lupus nephritis

 Class IV-G (C): Chronic inactive lesions with scars—diffuse global sclerosing

lupus nephritis

Class V: Membranous Lupus Nephritis

Global or segmental subepithelial immune deposits or their morphologic

sequelae by light microscopy and by immunofluorescence or electron

microscopy, with or without mesangial alterations. Class V lupus nephritis may

occur in combination with class III or IV, in which case both will be diagnosed.

Class V lupus nephritis may show advanced sclerosis.

Class VI: Advanced Sclerotic Lupus Nephritis

≥90% of glomeruli globally sclerosed without residual activity.

Note: Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial

inflammation and fibrosis, and severity of arteriosclerosis or other vascular lesions.

Source: Reproduced with permission from JJ Weening et al: The classification of

glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 65;521,

2004.

2740 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

most clinical studies in SLE for the next several years. An algorithm

for diagnosis and initial therapy is shown in Fig. 356-2. The criteria

are intended for diagnosis of SLE in subjects included in studies; the

authors use them in individual patients for estimating the probability

that a disease is SLE. In the SLICC criteria, any combination of four

or more well-documented criteria at any time during an individual’s

history, with at least one in the clinical and one in the immunologic

category, makes it likely that the patient has SLE (specificity 97%, sensitivity 84%%). For EULAR/ACR criteria, a subject must have a positive

ANA (≥1:80 by immunofluorescence) and a score of 10 (specificity

97%, sensitivity 93%). In many patients, criteria accrue over time. Antinuclear antibodies (ANAs) are positive in >98% of patients during the

course of disease; repeated negative tests by immunofluorescent methods suggest that the diagnosis is not SLE, unless other autoantibodies

are present (Fig. 356-2). High-titer IgG antibodies to double-stranded

DNA and antibodies to the Sm antigen are both specific for SLE and,

therefore, favor the diagnosis in the presence of compatible clinical

manifestations. The presence of multiple autoantibodies in an individual without clinical symptoms should not be considered diagnostic for

SLE, although such persons are at increased risk.

INTERPRETATION OF CLINICAL

MANIFESTATIONS

When a diagnosis of SLE is made, it is important to establish the severity

and potential reversibility of the illness and to estimate the possible consequences of various therapeutic interventions. In the following paragraphs, descriptions of some disease manifestations begin with relatively

mild problems and progress to those that are more life-threatening.

■ OVERVIEW AND SYSTEMIC MANIFESTATIONS

At its onset, SLE may involve one or several organ systems; over time,

additional manifestations may occur (Tables 356-3, 356-4, and 356-5).

Most of the autoantibodies characteristic of each person are present

at the time clinical manifestations appear (Tables 356-1, 356-3, and

356-4). Severity of SLE varies from mild and intermittent to severe

and fulminant. Systemic symptoms, particularly fatigue and myalgias/

arthralgias, are present most of the time. Severe systemic illness requiring high-dose glucocorticoid therapy can occur with fever, prostration,

weight loss, and anemia with or without other organ-targeted manifestations. Approximately 85% of patients have either continuing active

disease (on current treatment) or one or more flares of active disease

annually. Permanent complete remissions (absence of symptoms with

no treatment) occur in <5%. Recommended treatment target is remission on therapy (no clinical manifestations; abnormal laboratory tests

permitted) or induction of low lupus disease activity. See “Management

of Systemic Lupus Erythematosus,” below, for more detail.

■ MUSCULOSKELETAL MANIFESTATIONS

Most people with SLE have intermittent polyarthritis, varying from

mild to disabling. Polyarthritis is characterized by soft tissue swelling

and tenderness in joints and/or tendons, most commonly in hands,

wrists, and knees. Joint deformities (hands and feet) develop in only

10% and are often reducible. Erosions on joint x-rays are rare but can

be identified by ultrasound in 10–50% of patients; individuals with

erosions may fulfill criteria for both RA and SLE (“rhupus”). If pain

persists in a single joint, such as knee, shoulder, or hip, a diagnosis of

ischemic necrosis of bone (INB) should be considered, particularly

if there are no other manifestations of active SLE. INB prevalence is

increased in SLE, especially in patients treated with systemic glucocorticoids. Myositis with clinical muscle weakness, elevated creatine

kinase levels, positive magnetic resonance imaging (MRI) scan, and

muscle necrosis and inflammation on biopsy can occur, although most

patients have myalgias without frank myositis. Glucocorticoid therapies (commonly) and antimalarial therapies (rarely) can cause muscle

weakness; these adverse effects must be distinguished from active

inflammatory disease.

■ CUTANEOUS MANIFESTATIONS

Lupus dermatitis can be classified as acute, subacute, or chronic, and

there are many different types of lesions encompassed within these

groups. Discoid lupus erythematosus (DLE) is the most common

chronic dermatitis in lupus; lesions are roughly circular with slightly

raised, scaly, hyperpigmented erythematous rims and depigmented,

atrophic centers in which all dermal appendages are permanently

destroyed. Lesions can be disfiguring, particularly on the face and scalp.

Only 5% of people with DLE have SLE (although half have positive

ANA); however, among individuals with SLE, as many as 20% have DLE.

The most common acute SLE rash is a photosensitive, slightly raised,

occasionally scaly erythema on the face (particularly the cheeks and

nose—the “butterfly” rash), ears, chin, V region of the neck and chest,

upper back, and extensor surfaces of the arms. Worsening of this rash

often accompanies flare of systemic disease. Subacute cutaneous lupus

erythematosus (SCLE) consists of scaly red patches, similar to psoriasis,

or circular, flat, red-rimmed (“annular”) lesions. Patients with these

manifestations are exquisitely photosensitive; most have antibodies to

Ro (SS-A). Other SLE rashes include recurring urticaria, lichen planus–

like dermatitis, bullae, and panniculitis (“lupus profundus”). Rashes can

be minor or severe; they may be the major disease manifestation. Small

ulcerations on the oral or nasal mucosa are common in SLE; the lesions

resemble aphthous ulcers and may or may not be painful.

■ RENAL MANIFESTATIONS

Nephritis is usually the most serious manifestation of SLE, particularly

because nephritis and infection are the leading causes of mortality

in the first decade of disease. Because nephritis is asymptomatic in

most lupus patients, urinalysis should be ordered in any person suspected of having SLE. The classification of lupus nephritis is primarily

histologic (see “Pathology,” above, and Table 356-2). Renal biopsy

TABLE 356-3 Systemic Lupus International Collaborating Clinic

Criteria for Classification of Systemic Lupus Erythematosus

CLINICAL MANIFESTATIONS

IMMUNOLOGIC

MANIFESTATIONS

Skin

 Acute, subacute cutaneous LE

(photosensitive, malar, maculopapular,

bullous)

 Chronic cutaneous LE (discoid lupus,

panniculitis, lichen planus–like,

hypertrophic verrucous, chillblains)

Oral or nasal ulcers

Nonscarring alopecia

Synovitis involving ≥2 joints

Serositis (pleurisy, pericarditis)

Renal

Prot/Cr ≥0.5

RBC casts

Biopsya

Neurologic

 Seizures, psychosis, mononeuritis,

myelitis, peripheral or cranial

neuropathies, acute confusional state

Hemolytic anemia

Leukopenia (<4000/μL) or lymphopenia

(<1000/μL)

Thrombocytopenia (<100,000/μL)

ANA > reference negative value

Anti-dsDNA > reference, if by

ELISA 2× reference

Anti-Sm

Antiphospholipid (any of lupus

anticoagulant, false-positive RPR,

anticardiolipin, anti–

β2

-glycoprotein 1)

Low serum complement (C3, C4,

or CH50)

Positive direct Coombs test

a

Renal biopsy read as systemic lupus qualifies for classification as SLE if any lupus

autoantibodies are present, even if total criteria are fewer than 4.

Interpretation: Presence of any four criteria (must have at least 1 in each category)

qualifies patient to be classified as having SLE with 93% specificity and 92%

sensitivity. American College of Rheumatology is developing new criteria for SLE.

For update, see website Rheumatology.org.

Abbreviations: ANA, antinuclear antibody; Cr, creatinine; ELISA, enzyme-linked

immunosorbent assay; LE, lupus erythematosus; Prot, protein; RBC, red blood cell;

RPR, rapid plasma reagin.

Source: M Petri et al: Arthritis Rheum 64:2677, 2012. Because these criteria are

relatively new, some currently ongoing clinical studies use prior American College

of Rheumatology Criteria; see EM Tan et al: Arthritis Rheum 25:1271, 1982; update

MC Hochberg: Arthritis Rheum 40:1725, 1997.

Systemic Lupus Erythematosus

2741CHAPTER 356

is recommended for every SLE patient with any clinical evidence of

nephritis; results are used to plan current therapies and their duration.

Patients with dangerous proliferative forms of glomerular damage (ISN

III and IV) usually have microscopic hematuria and proteinuria (>500

mg per 24 h); approximately one-half develop nephrotic syndrome,

and most develop hypertension. Overall, in the United States, ~20% of

individuals with lupus diffuse proliferative glomerulonephritis (DPGN)

die or develop ESRD within 10 years of diagnosis. Such individuals

require aggressive control of SLE and of the complications of renal

disease and of therapy unless damage is irreversible (Fig. 356-2, Table

356-6). African Americans, Hispanics, and Asians/Pacific Islanders are

more likely to develop nephritis than Caucasians. African Americans

are more likely to develop ESRD than are whites, even with the most

current therapies. Approximately 20% of SLE patients with proteinuria

(usually nephrotic) have membranous glomerular changes without

proliferative changes on renal biopsy. Their outcome is better than for

those with DPGN, but patients with class V and nephrotic range proteinuria should be treated in the same way as those with classes III or

IV proliferative disease. Lupus nephritis is usually an ongoing disease,

with flares requiring re-treatment or increased treatment over many

years. For most people with lupus nephritis, accelerated atherosclerosis

becomes important after several years of disease; attention must be

given to control of systemic inflammation, blood pressure, hyperlipidemia, and hyperglycemia.

■ NERVOUS SYSTEM MANIFESTATIONS

There are many central nervous system (CNS) and peripheral nervous system manifestations of SLE; in some patients, these are the

major cause of morbidity and mortality. It is useful to approach this

diagnostically by asking first whether the symptoms result from SLE

or another condition (such as infection in immunosuppressed individuals or side effects of therapies). If symptoms are related to SLE,

it should be determined whether they are caused by a diffuse process

(requiring immunosuppression) or vascular occlusive disease (requiring anticoagulation). The most common manifestation of diffuse CNS

lupus is cognitive dysfunction, including difficulties with memory and

reasoning. Headaches are also common. When excruciating, they often

indicate SLE flare; when milder, they are difficult to distinguish from

migraine or tension headaches. Seizures of any type may be caused by

lupus; treatment often requires both antiseizure and immunosuppressive therapies. Psychosis can be the dominant manifestation of SLE;

it must be distinguished from glucocorticoid-induced psychosis. The

latter usually occurs in the first weeks of glucocorticoid therapy, at daily

doses of ≥40 mg of prednisone or equivalent; psychosis resolves over

several days after glucocorticoids are decreased or stopped. Myelopathy is often disabling; rapid initiation of immunosuppressive therapy

including high-dose glucocorticoids is standard of care.

■ VASCULAR OCCLUSIONS INCLUDING STROKE

AND MYOCARDIAL INFARCTIONS

The prevalence of transient ischemic attacks, strokes, and myocardial

infarctions is increased in patients with SLE. These vascular events

are increased in, but not exclusive to, SLE patients with antibodies to

phospholipids (antiphospholipid antibodies) (Chap. 357). Ischemia in

the brain can be caused by focal occlusion (either noninflammatory

or associated with vasculitis) or by embolization from carotid artery

TABLE 356-4 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus (SLE)

Positive ANA (titer at least 1:80) is obligatory entry criterion, followed by additive weighted criteria in 7 clinical and 3 immunologic

domains. Accumulating ≥10 points classifies as SLE.

All manifestations must be attributable to SLE.

CLINICAL CRITERIA

DOMAIN CRITERIA % OF PATIENTS WITH FEATUREa WEIGHT

Constitutional, 80% Fever 50 2

Hematologic, 50% Leukopenia 30 3

Thrombocytopenia 20 4

Autoimmune hemolytic anemia 10 4

Neuropsychiatric, 75% Delirium 5 2

Psychosis 7 3

Seizure 11 5

Mucocutaneous, 80% Nonscarring alopecia 15 2

Oral ulcers 45 2

Subcutaneous or discoid lupus 30 4

Acute cutaneous lupus 70 6

Serosal, 50% Pleural or pericardial effusion 50 5

Acute pericarditis 35 6

Musculoskeletal, 95% Joint involvement 90 6

Renal, 50% Proteinuria >0.5 g/24 h 50 4

Renal biopsy class II or V LN 25% of LN 8

Renal biopsy class III or IV LN 60% of LN 10

IMMUNOLOGIC CRITERIA

DOMAIN CRITERIA % OF PATIENTS WITH FEATUREa WEIGHT

Antiphospholipids + Anticardiolipin, anti–β2

-glycoprotein, or lupus

anticoagulant (LAC)

40 2

Complements Low C3 or C4 35 3

Low C3 and C4 30 4

SLE-specific antibodies Anti-dsDNA or anti-Smith antibodies 40 6

a

Percentage of SLE patients exhibiting the criterion at any time during disease. Estimated from data provided in pertinent chapters in Wallace DJ, Hahn BH (eds): Dubois’

Lupus Erythematosus and Related Syndromes, 9th ed. Philadelphia, Elsevier, 2019.

Abbreviations: ACR, American College of Rheumatology; ANA, antinuclear antibody; EULAR, European Union League Against Rheumatism; LN, lupus nephritis.

2742 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

plaque or from vegetations of Libman-Sacks endocarditis. Appropriate tests for antiphospholipid antibodies (see below) and for sources

of emboli should be ordered in such patients to estimate the need

for, intensity of, and duration of anti-inflammatory and/or anticoagulant therapies. When it is most likely that a cerebral event results

from clotting, long-term anticoagulation is the therapy of choice.

Two processes can occur at once—vasculitis plus bland vascular

occlusions—in which case it is appropriate to treat with anticoagulation plus immunosuppression.

In SLE, myocardial infarctions are primarily manifestations of accelerated atherosclerosis. The increased risk for vascular events is threeto tenfold overall and is highest in women aged <49 years compared

to age-matched controls. Characteristics associated with increased

risk for atherosclerosis include male gender, older age, hypertension,

dyslipidemia, diabetes, dysfunctional proinflammatory high-density

lipoproteins, high disease activity, high glucocorticoid dose, and high

serum homocysteine and leptin. Statin therapies reduce levels of

low-density lipoproteins (LDL) in SLE patients; significant reduction

of all-cause mortality by statins has been shown in SLE patients with

renal transplants and in an epidemiologic study of a large number of

patients in Taiwan.

■ PULMONARY MANIFESTATIONS

The most common pulmonary manifestation of SLE is pleuritis with or

without pleural effusion. This manifestation, when mild, may respond

to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs);

Diagnosis: Symptom complex suggestive of SLE

Order laboratory tests: ANA, CBC, platelets, urinalysis

All tests normal

symptoms subside

All tests normal

symptoms persist

ANA positive

Not SLE

Not SLE

Treatment

Repeat ANA, add

anti-dsDNA, anti-Ro

All negative Some positive Definite SLE (≥4

criteria, Table 356-3)

Possible SLE (<4

criteria, Table 356-3)

Not life- or organ-threatening Life- or organ-threatening

Quality of life:

Acceptable

Quality of life:

Not acceptable

High-dose glucocorticoids, usually

with addition of second agent

Conservative management (Table 356-6)

Conservative treatment plus

low-dose glucocorticoids

Consider belimumab or

anifrolumab

Mycophenolate

mofetil

(or myfortic acid)

Cyclophosphamide

Low or high dose

Do not exceed

6 months of Rx

In lupus nephritis

mycophenolate

plus calcineurin

inhibitor (tacrolimus,

voclosporin) may be

used instead of MMF

alone or

cyclophosphamide

After response, d/c cyclophosphamide;

maintain with mycophenolate or azathioprine

No response Response

Taper dose of all

agents, especially

glucocorticoids

Belimumab, rituximab,

calcineurin inhibitors, or

experimental therapies

FIGURE 356-2 Algorithm for diagnosis and initial therapy of systemic lupus erythematosus (SLE). For guidelines on management of lupus and lupus nephritis, see

Fanouriakis A et al: 2019 Update of the EULAR/ACR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 78:736, 2019; Hahn BH et

al: American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 64:797, 2012; Tunnicliffe DJ

et al: Immunosuppressive treatment for proliferative lupus nephritis. Cochrane Database Syst Rev 29:CD002922, 2018. For belimumab, see Stohl W: Inhibition of B cell

activating factor (BAFF) in the management of systemic lupus erythematosus (SLE). Expert Rev Clin Immunol 13:163, 2017 and Furie R et al: Two-year, randomized, controlled

trial of belimumab in lupus nephritis. New Eng J Med 383:1117, 2020. For rituximab, and other current experimental therapies, see Davis LS, Reimold AM: Research and

therapeutics-traditional and emerging therapies in systemic lupus erythematosus. Rheumatology (Oxford) 56(Suppl 1):1100, 2017. For tacrolimus and triple therapy, see Liu Z

et al: Multitarget therapy for induction treatment of lupus nephritis: A randomized trial. Ann Intern Med 162:18, 2015. For voclosporin see Rovin BH et al: Efficacy and safety

of voclosporin versus placebo for lupus nephritis: a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet published May 7, 2021. For Anifrolumab

see Morand EF et al: Trial of anifrolumab in active systemic lupus erythematosus. N Eng J Med 382:211, 2020. ANA, antinuclear antibodies; CBC, complete blood count; MMF,

mycophenolate mofetil; Rx, therapy; SLE, systemic lupus erythematosus.

Systemic Lupus Erythematosus

2743CHAPTER 356

TABLE 356-5 Clinical Manifestations of SLE and Prevalence

over the Entire Course of Diseasea

MANIFESTATION PREVALENCE, %

Systemic: Fatigue, malaise, fever, anorexia, weight loss 95

Musculoskeletal 95

Arthralgias/myalgias 95

Polyarthritis 60

Hand deformities 10

Myopathy/myositis 25/5

Ischemic necrosis of bone 15

Cutaneous 80

Photosensitivity 70

Malar rash 50

Oral ulcers 40

Alopecia 40

Discoid rash 20

Vasculitis rash 20

Other (e.g., urticaria, subacute cutaneous lupus) 15

Hematologic 85

Anemia (chronic disease) 70

Leukopenia (<4000/μL) 65

Lymphopenia (<1500/μL) 50

Thrombocytopenia (<100,000/μL) 15

Lymphadenopathy 15

Splenomegaly 15

Hemolytic anemia 10

Neurologic 60

Cognitive disorder 50

Mood disorder 40

Depression 25

Headache 25

Seizures 20

Mono-, polyneuropathy 15

Stroke, TIA 10

Acute confusional state or movement disorder 2–5

Aseptic meningitis, myelopathy <1

Cardiopulmonary 60

Pleurisy, pericarditis, effusions 30–50

Myocarditis, endocarditis 10

Lupus pneumonitis 10

Coronary artery disease 10

Interstitial fibrosis 5

Pulmonary hypertension, ARDS, hemorrhage <5

Shrinking lung syndrome <5

Renal 30–50

Proteinuria ≥500 mg/24 h, cellular casts 30–60

Nephrotic syndrome 25

End-stage renal disease 5–10

Gastrointestinal 40

Nonspecific (nausea, mild pain, diarrhea) 30

Abnormal liver enzymes 40

Vasculitis 5

Thrombosis 15

Venous 10

Arterial 5

Ocular 15

Sicca syndrome 15

Conjunctivitis, episcleritis 10

Vasculitis 5

a

Numbers indicate percentage of patients who have the manifestation at some time

during the course of illness.

Abbreviations: ARDS, acute respiratory distress syndrome; SLE, systemic lupus

erythematosus; TIA, transient ischemic attack.

when more severe, patients require a brief course of glucocorticoid

therapy. Pulmonary infiltrates also occur as a manifestation of active

SLE and are difficult to distinguish from infection on imaging studies.

Life-threatening pulmonary manifestations include interstitial inflammation leading to fibrosis (histologic pattern mimics usual diffuse

interstitial pneumonitis), shrinking lung syndrome, and intra-alveolar

hemorrhage; all of these probably require early aggressive immunosuppressive therapy as well as supportive care. Pulmonary arterial

hypertension occurs in a small proportion of SLE patients and should

be treated in the same way as idiopathic pulmonary hypertension.

■ CARDIAC MANIFESTATIONS

Pericarditis is the most frequent cardiac manifestation; it usually

responds to anti-inflammatory therapy and infrequently leads to

tamponade. More serious cardiac manifestations are myocarditis and

fibrinous endocarditis of Libman-Sacks. Myocardial inflammation

can be associated with left ventricular dysfunction and heart failure.

Overall, lupus patients have a 2.7-fold higher risk of developing heart

failure compared with the general population. Arrhythmias are frequent. Endocardial involvement can lead to valvular insufficiencies,

most commonly of the mitral or aortic valves, or to embolic events. It

has not been proven that glucocorticoid or other immunosuppressive

therapies lead to improvement of lupus myocarditis or endocarditis,

but it is usual practice to administer a trial of high-dose steroids along

with appropriate supportive therapy for heart failure, arrhythmia, or

embolic events. As discussed above, patients with SLE are at increased

risk for myocardial infarction, usually due to accelerated atherosclerosis, which probably results from immune attack, chronic inflammation,

and/or chronic oxidative damage to arteries.

■ HEMATOLOGIC MANIFESTATIONS

The most frequent hematologic manifestation of SLE is anemia, usually

normochromic normocytic, reflecting chronic illness and consequent

impaired utilization of iron. Hemolysis can be rapid in onset and

severe, requiring high-dose glucocorticoid therapy. Leukopenia is

also common and almost always consists of lymphopenia, not granulocytopenia; lymphopenia rarely predisposes to infections and by

itself usually does not require therapy. Thrombocytopenia may be a

recurring problem. If platelet counts are >40,000/μL and abnormal

bleeding is absent, therapy may not be required. High-dose glucocorticoid therapy (e.g., 1 mg/kg per day of prednisone or equivalent) is

usually effective for the first few episodes of severe thrombocytopenia.

Recurring or prolonged hemolytic anemia or thrombocytopenia, or

disease requiring an unacceptably high dose of daily glucocorticoids,

should be treated with additional strategies such as rituximab, platelet

growth factors, and/or splenectomy (see “Management of Systemic

Lupus Erythematosus” below).

■ GASTROINTESTINAL MANIFESTATIONS

Nausea, sometimes with vomiting, and diarrhea can be manifestations

of an SLE flare. Diffuse abdominal pain can be caused by autoimmune

peritonitis and/or intestinal vasculitis. Increases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

are common when SLE is active. These manifestations usually improve

promptly during systemic glucocorticoid therapy. Vasculitis involving

the intestine can be life-threatening; perforations, ischemia, bleeding,

and sepsis are frequent complications. Aggressive immunosuppressive

therapy with high-dose glucocorticoids is recommended for shortterm control; evidence of recurrence is an indication for additional

immunosuppression.

■ OCULAR MANIFESTATIONS

Sicca syndrome (Sjögren’s syndrome; Chap. 361) and nonspecific conjunctivitis are common in SLE and rarely threaten vision. In contrast,

retinal vasculitis and optic neuritis are serious manifestations: blindness can develop over days to weeks. Aggressive immunosuppression

is recommended, although there are no controlled trials to prove effectiveness. Complications of systemic and intraorbital glucocorticoid

therapy include cataracts (common) and glaucoma.

2744 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 356-6 Medications for the Management of SLE

MEDICATION DOSE RANGE DRUG INTERACTIONS SERIOUS OR COMMON ADVERSE EFFECTS

NSAIDs, salicylates

(Ecotrina

 and St. Joseph’s

aspirina

 approved by FDA

for use in SLE)

Doses toward upper limit of

recommended range usually

required

A2R/ACE inhibitors, glucocorticoids,

fluconazole, methotrexate, thiazides

NSAIDs: Higher incidence of aseptic meningitis,

elevated liver enzymes, decreased renal function,

vasculitis of skin; entire class, especially COX2-specific inhibitors, may increase risk for

myocardial infarction

Salicylates: ototoxicity, tinnitus

Both: GI events and symptoms, allergic reactions,

dermatitis, dizziness, acute renal failure, edema,

hypertension

Topical glucocorticoids Mid potency for face; mid to high

potency for other areas

None known Atrophy of skin, contact dermatitis, folliculitis,

hypopigmentation, infection

Topical sunscreens SPF 15 at least; 30+ preferred None known Contact dermatitis

Hydroxychloroquinea

(quinacrine can be added

or substituted)

200–400 mg qd (100 mg qd); do not

exceed 5.0 mg/kg actual weight

Contraindicated use with QT-prolonging

agents (e.g., donepezil, amiodarone) and with

aurothioglucose. Caution with cyclosporine,

cimetidine, digoxin, ampicillin, lanthanum,

antacids, kaolin.

Retinal damage, agranulocytosis, aplastic anemia,

ataxia, cardiomyopathy, dizziness, myopathy,

ototoxicity, peripheral neuropathy, pigmentation

of skin, seizures, thrombocytopenia; quinacrine

usually causes diffuse yellow skin coloration

DHEA

(dehydroepiandrosterone)

200 mg qd Unclear Acne, menstrual irregularities, high serum levels of

testosterone

Methotrexate (for

dermatitis, arthritis)

10–25 mg once a week, PO or SC,

with folic acid; decrease dose if CrCl

<60 mL/min

Acitretin, leflunomide, NSAIDs and

salicylates, penicillins, probenecid,

sulfonamides, trimethoprim. Caution with

interventions that can suppress bone marrow

or cause liver toxicity.

Anemia, bone marrow suppression, leukopenia,

thrombocytopenia, hepatotoxicity, nephrotoxicity,

infections, neurotoxicity, pulmonary fibrosis,

pneumonitis, severe dermatitis, seizures,

pseudolymphoma

Glucocorticoids, orala

(several specific brands

are approved by FDA for

use in SLE)

Prednisone, prednisolone: 0.5–1 mg/

kg per day for severe SLE 0.07–0.3

mg/kg per day or qod for milder

disease. Taper to 7.5 mg daily or less

if possible.

A2R/ACE antagonists, antiarrhythmics

class III, cyclosporine, NSAIDs and

salicylates, phenothiazines, phenytoins,

quinolones, rifampin, risperidone, thiazides,

sulfonylureas, warfarin

Infection, VZV infection, hypertension,

hyperglycemia, hypokalemia, acne, allergic

reactions, anxiety, aseptic necrosis of bone,

cushingoid changes, CHF, fragile skin, insomnia,

menstrual irregularities, mood swings,

osteoporosis, psychosis

Methylprednisolone

sodium succinate, IVa

(FDA approved for lupus

nephritis)

For severe disease, 0.5–1 g IV qd ×

3 days

As for oral glucocorticoids As for oral glucocorticoids (if used repeatedly);

anaphylaxis

Cyclophosphamideb

 IV Low dose (for whites of northern

European backgrounds): 500 mg

every 2 weeks for 6 doses, then

begin maintenance with MMF or

AZA.

High dose: 7–25 mg/kg every

month × 6; consider mesna

administration with dose

Allopurinol, bone marrow suppressants,

colony-stimulating factors, doxorubicin,

rituximab, succinylcholine, zidovudine

Infection, VZV infection, bone marrow suppression,

leukopenia, anemia, thrombocytopenia,

hemorrhagic cystitis (less with IV), carcinoma of

the bladder, alopecia, nausea, diarrhea, malaise,

malignancy, ovarian and testicular failure. Ovarian

failure is probably not a problem with low dose.

Oral cyclophosphamide 1.5–3 mg/kg per day; decrease dose

for CrCl <25 mL/min

Mycophenolate mofetil

(MMF)b

 or mycophenolic

acid (MPA)

MMF: 2–3 g/d PO total given bid for

induction therapy, 1–2 g/d total given

bid for maintenance therapy; max

1 g bid if CrCl <25 mL/min. Begin with

low dose and increase every 1–2

weeks to minimize GI side effects.

Start treatment at 0.5 g bid. If used

with calcineurin inhibitor, target dose

of mycophenolate is 1 g bid.

MPA: 360–1080 mg bid; caution if

CrCl <25 mL/min

Acyclovir, antacids, azathioprine, bile

acid–binding resins, ganciclovir, iron, salts,

probenecid, oral contraceptives

Infection, leukopenia, anemia, thrombocytopenia,

lymphoma, lymphoproliferative disorders,

malignancy, alopecia, cough, diarrhea, fever,

GI symptoms, headache, hypertension,

hypercholesterolemia, hypokalemia, insomnia,

peripheral edema, elevated liver enzymes, tremor,

rash. Limited data suggest Asians should begin

treatment with doses not exceeding 2 g daily to

reduce adverse events.

Azathioprine (AZA)b 2–3 mg/kg per day PO for induction;

1–2 mg/kg per day for maintenance;

decrease frequency of dose if CrCl

<50 mL/min

ACE inhibitors, allopurinol, bone marrow

suppressants, interferons, mycophenolate

mofetil, rituximab, warfarin, zidovudine

Infection, VZV infection, bone marrow suppression,

leukopenia, anemia, thrombocytopenia,

pancreatitis, hepatotoxicity, malignancy, alopecia,

fever, flulike illness, GI symptoms

Belimumab 10 mg/kg IV weeks 0, 2, and 4, then

monthly or subcutaneous 200 mg

each week

IVIg, live vaccines (contraindicated),

tofacitinib

Infusion reactions, allergy, infections, headache

and diffuse body aching

Rituximab (for patients

resistant to above

therapies)

375 mg/m2

 every week × 4 or 1 g

every 2 weeks × 2

IVIg, live vaccines (contraindicated),

infliximab, cisplatin (renal failure), tofacitinib

Infection (including PML), infusion reactions,

headache, arrhythmias, allergic responses

(Continued)

Systemic Lupus Erythematosus

2745CHAPTER 356

TABLE 356-6 Medications for the Management of SLE

MEDICATION DOSE RANGE DRUG INTERACTIONS SERIOUS OR COMMON ADVERSE EFFECTS

Tacrolimus Trough blood level should not exceed

5.5 ng/mL to minimize toxicity. Begin

dose at 1 mg bid

Increases risk for QT interval prolongation

(e.g., hydroxychloroquine); interferes

with drugs using CYP3A pathway; caution

with fluconazole, ritonavir, voriconazole,

clotrimazole, metronidazole, omeprazole,

fentanyl, ketoconazole, caspofungin,

amiodarone. Do not ingest grapefruit or

pomegranate juice while taking tacrolimus.

Infection, nephrotoxicity, neural toxicity

Voclosporin with MMF

Three 7.9 mg capsules bid, do not

use if GFR <45 mL/min

Do not use with strong CYP3A4 inhibitors/

inducers

Do not use with cytoxan

Infection, hypertension, hyper kalemia, decrease

GFR, tremor

May cause fetal harm.

Anifrolumab 300 mg i.v. every 4 weeks Do not use with other biologics

Reduce dose if eGFR is less than 60 mL/

min/1.73 m2

 BSA

Infection, herpes zoster, bronchitis, infusion

reactions, anaphylaxis

a

Indicates medication is approved for use in SLE by the U.S. Food and Drug Administration. b

Indicates the medication has been used with glucocorticoids in the trials

showing efficacy.

Abbreviations: A2R, angiotensin II receptor; ACE, angiotensin-converting enzyme; CHF, congestive heart failure; CrCl, creatinine clearance; FDA, U.S. Food and Drug

Administration; GI, gastrointestinal; IVIg, intravenous immunoglobulin; NSAIDs, nonsteroidal anti-inflammatory drugs; PML, progressive multifocal leukoencephalopathy;

SLE, systemic lupus erythematosus; SPF, sun protection factor; VZV, varicella-zoster virus.

(Continued)

LABORATORY TESTS

Laboratory tests serve (1) to establish or rule out the diagnosis; (2) to

follow the course of disease and, in particular, to suggest that a flare is

occurring or organ damage is developing; and (3) to identify adverse

effects of therapies.

■ TESTS FOR AUTOANTIBODIES (TABLES 356-1 AND 356-3)

Diagnostically, the most important autoantibodies are ANA because the

test is positive in >95% of patients, usually at the onset of symptoms. A

few patients develop ANA within 1 year of symptom onset; repeated

testing may thus be useful. ANA tests using immunofluorescent

methods are more reliable than enzyme-linked immunosorbent assays

(ELISAs) and/or bead assays, which have less specificity. ANA-negative

lupus exists but is rare in adults and is usually associated with other

autoantibodies (anti-Ro or anti-DNA). High-titer IgG antibodies to

double-stranded DNA (dsDNA) (but not to single-stranded DNA) are

specific for SLE. ELISA and immunofluorescent reactions of sera with

the dsDNA in the flagellate Crithidia luciliae have ~60% sensitivity for

SLE. Titers of anti-dsDNA vary over time. In some patients, increases

in quantities of anti-dsDNA herald a flare, particularly of nephritis or

vasculitis, and especially when associated with declining levels of C3 or

C4 complement. Antibodies to Sm are also specific for SLE and assist

in diagnosis; anti-Sm antibodies do not usually correlate with disease

activity or clinical manifestations. Antiphospholipid antibodies are not

specific for SLE, but their presence fulfills one classification criterion,

and they identify patients at increased risk for venous or arterial clotting,

thrombocytopenia, and fetal loss. There are three widely accepted tests

that measure different antibodies (anticardiolipin, anti-β2

-glycoprotein, and the lupus anticoagulant). ELISA is used for anticardiolipin

and anti-β2

-glycoprotein (both internationally standardized with good

reproducibility); a sensitive phospholipid-based activated prothrombin

time such as the dilute Russell venom viper test is used to identify the

lupus anticoagulant. The higher the titers of IgG anticardiolipin (>40 IU

is considered high), and the greater the number of different antiphospholipid antibodies that are detected, the greater is the risk for a clinical

episode of clotting. Quantities of antiphospholipid antibodies may vary

markedly over time; repeated testing is justified if clinical manifestations

of the antiphospholipid syndrome (APS) appear (Chap. 357). To classify

a patient as having APS, with or without SLE, by international criteria

requires the presence of one or more clotting episodes and/or repeated

fetal losses plus at least two positive tests for antiphospholipid antibodies, at least 12 weeks apart; however, many patients with APS do not

meet these stringent criteria, which are intended forinclusion of patients

into studies.

An additional autoantibody test with predictive value (not used for

diagnosis) detects anti-Ro/SS-A, which indicates increased risk for

neonatal lupus, sicca syndrome, and SCLE. Women with child-bearing

potential and SLE should be screened for antiphospholipid antibodies and

anti-Ro, because both antibodies have the potential to cause fetal harm.

Antibodies to C1q are not specific or sensitive for SLE; however,

they are highly associated with active lupus nephritis and may fluctuate

as the activity of nephritis changes.

■ STANDARD TESTS FOR DIAGNOSIS

Screening tests for complete blood count, platelet count, and urinalysis

may detect abnormalities that contribute to the diagnosis and influence

management decisions.

■ TESTS FOR FOLLOWING DISEASE COURSE

It is useful to follow tests that indicate the status of organ involvement known to be present during SLE flares. These might include

urinalysis for hematuria and proteinuria, hemoglobin levels, platelet

counts, and serum levels of creatinine or albumin. There is great interest in identification of additional markers of disease activity. Candidates include levels of anti-DNA and anti-C1q antibodies, several

components of complement (C3 is most widely available), activated

complement products (an assay is commercially available that measures

binding to the C4d receptor on erythrocytes and B cells), IFN-inducible gene expression in peripheral blood cells, serum levels of BLyS

(B lymphocyte stimulator, also called BAFF), and urinary levels of

TNF-like weak inducer of apoptosis (TWEAK), neutrophil gelatinaseassociated lipocalin (NGAL), or monocyte chemotactic protein 1 (MCP1). None is uniformly agreed upon as a reliable indicator of flare or of

response to therapeutic interventions. It is likely that a panel of multiple

proteins and nuclear products (and possibly levels of selected miRNAs

and methylation profiles of DNA) will be developed to predict both

impending flare and response to recently instituted therapies. Increased

quantities of plasma cells, and increased expression of their gene signatures in whole blood, are associated with active disease and flares, but

measurements are not commercially available. For now, the physician

should determine for each patient whether certain available laboratory

test changes predict flare (falling complement, rising anti-DNA, increased

proteinuria, worsening anemia, etc.). If so, altering therapy in response to

these changes may be advisable (30 mg of prednisone daily for 2weeks has

been shown to prevent flares in patients with rising anti-DNA plus falling

complement). In addition, given the increased prevalence of atherosclerosis in SLE, it is advisable to follow the recommendations of the National

Cholesterol Education Program for testing and treatment, including

scoring of SLE as an independent risk factor, similar to diabetes mellitus.

MANAGEMENT OF SYSTEMIC LUPUS

ERYTHEMATOSUS

There is no cure for SLE, and complete sustained remissions are rare.

There is an international effort to encourage practitioners and patients

to aim for low-level disease activity (LLDAS), meaning mild symptoms