Systemic Lupus Erythematosus:​

Diagnosis and Treatment

Nguyet-Cam V. Lam, MD;​Judy Abu Brown, MD;​and Richa Sharma, MD
St. Luke’s Bethlehem Family Medicine Residency, St. Luke’s University Hospital, Bethlehem, Pennsylvania

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects the cardiovascular, gastrointestinal, hematologic,
integumentary, musculoskeletal, neuropsychiatric, pulmonary, renal, and reproductive systems. It is a chronic disease and
may cause recurrent flare-ups without adequate treatment. The newest clinical criteria proposed by the European League
Against Rheumatism/American College of Rheumatology in 2019 include an obligatory entry criterion of a positive antinu-
clear antibody titer of 1:​80 or greater. Management of SLE is directed at complete remission or low disease activity, minimizing
the use of glucocorticoids, preventing flare-ups, and improving quality of life. Hydroxychloroquine is recommended for all
patients with SLE to prevent flare-ups, organ damage, and thrombosis and increase long-term survival. Pregnant patients
with SLE have an increased risk of spontaneous abortions, stillbirths, preeclampsia, and fetal growth restriction. Precon-
ception counseling regarding risks, planning the timing of pregnancy, and a multidisciplinary approach play a major role in
the management of SLE in patients contemplating pregnancy. All patients with SLE should receive ongoing education, coun-
seling, and support. Those with mild SLE can be monitored by a primary care physician in conjunction with rheumatology.
Patients with increased disease activity, complications, or adverse effects from treatment should be managed by a rheuma-
tologist. (Am Fam Physician. 2023;​107(4):​383-395. Copyright © 2023 American Academy of Family Physicians.)

Systemic lupus erythematosus (SLE) is an autoim- SLE if they have four or more of the 11 symptoms.2,3 How-
mune disease that affects multiple organ systems. Its course ever, it was noted that not all patients meeting the criteria
is typically recurrent, with periods of relative remission fol- will have lupus and not all patients with clinically diag-
lowed by flare-ups. SLE can affect anyone, but it is more nosed lupus will meet the threshold criteria of four or more
common in women between 15 and 44 years of age. The of the 11 symptoms.4,5 Because of this, the Systemic Lupus
incidence and prevalence of SLE in North America are International Collaborating Clinics (SLICC) proposed new
23.2 per 100,000 person-years and 241 per 100,000 people, criteria in 2012.6 According to the SLICC criteria, patients
respectively.1 must meet at least four criteria, including at least one clin-
ical and one immunologic criterion, or the patient should
Classification Criteria have a biopsy confirming lupus nephritis and elevated
Clinicians should have high suspicion for SLE in patients
with symptoms involving multiple organ systems. Three WHAT’S NEW ON THIS TOPIC
classification approaches have evolved and provide some
perspective on features of the disease, but these are
not diagnostic criteria. These classification criteria are Systemic Lupus Erythematosus
designed to standardize patients for entry into clinical The newest clinical criteria proposed by the European League
trials. However, these criteria are often used clinically to Against Rheumatism/American College of Rheumatology in
2019 include an obligatory entry criterion:​a positive antinu-
evaluate patients. clear antibody titer of 1:​80 or greater.
Based on the 1997 update of the 1982 American College
of Rheumatology (ACR) criteria, patients meet criteria for Patients with chronic kidney disease should receive one
dose of pneumococcal conjugate vaccine (PCV20 or PCV15).
When PCV15 is used, it should be followed by a dose of pneu-
CME This clinical content conforms to AAFP criteria for mococcal polysaccharide vaccine (PPSV23).
CME. See CME Quiz on page 348.
Anifrolumab (Saphnelo) and voclosporin (Lupkynis) are new
Author disclosure:​No relevant financial relationships. medications approved by the U.S. Food and Drug Admin-
Patient information:​A handout on this topic is available istration in 2021 for the management of systemic lupus
with the online version of this article. erythematosus.

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 SYSTEMIC LUPUS ERYTHEMATOSUS

antinuclear antibody (ANA) or anti–double-stranded DNA The newest clinical criteria proposed by the European
(anti-dsDNA) levels without any other criteria.6 The SLICC League Against Rheumatism/American College of Rheu-
criteria have increased sensitivity (97%) and decreased matology (EULAR/ACR) in 2019 include an obligatory
specificity (84%) compared with the ACR criteria.6 entry criterion of a positive ANA titer of 1:​80 or greater.

TABLE 1

Criteria for Classifying Systemic Lupus Erythematosus

System ACR criteria (1997)* SLICC criteria (2012)† EULAR/ACR (2019)‡

Cardiovascular/ Pleuritis (pleuritic pain or Serositis (pleurisy for more than one Pleural or pericardial effusion (5);​
pulmonary rub or pleural effusion) or day, pleural effusion, or pleural rub;​ acute pericarditis (6)
pericarditis (documented by pericardial pain for more than one day,
electrocardiography, rub, or pericardial effusion, pericardial rub, or
pericardial effusion) pericarditis)

Constitutional — — Fever > 100.9°F (38.3°C) (2)

Hematologic Hemolytic anemia, leukope- Hemolytic anemia;​leukopenia (< 4,000 Leukopenia (3);​thrombocytopenia
nia (< 4,000 cells per mm3), cells per mm3) more than once or (4);​autoimmune hemolysis (4)
lymphopenia (< 1,500 cells lymphopenia (< 1,000 cells per mm3)
per mm3), or thrombocytope- more than once;​thrombocytopenia
nia (< 100,000 cells per mm3) (< 100,000 cells per mm3)

Immunologic Positive test result for anti- Positive test result for antinuclear Anticardiolipin immunoglobulin G
nuclear antibodies;​elevated antibodies;​elevated anti-dsDNA, anti- or anti-beta 2 -glycoprotein 1 anti-
anti-dsDNA, anti-Smith, or Smith, or antiphospholipid antibodies;​ bodies or lupus anticoagulant (2);​
antiphospholipid antibodies;​ low complement (C3, C4, or CH 50) or low C3 or C4 (3);​low C3 and low
discoid rash;​ photosensitivity;​ direct Coombs test (in the absence of C4 (4);​anti-dsDNA or anti-Smith
oral or nasal ulcers hemolytic anemia);​chronic cutaneous antibodies (6)
lupus, nonscarring alopecia, or oral or
nasal ulcers

Integumentary/ Malar rash Acute cutaneous lupus or subacute Nonscarring alopecia (2);​oral ulcers
mucosal cutaneous lupus (2);​subacute cutaneous or discoid
lupus (4);​acute cutaneous lupus (6)

Musculoskeletal Nonerosive arthritis involving Synovitis involving two or more joints Joint involvement (6)
two or more joints or tenderness at two or more joints and
at least 30 minutes of stiffness in the
morning

Neuropsychiatric Seizure or psychosis Seizure, psychosis, mononeuritis com- Delirium (2);​psychosis (3);​seizure (5)
plex, myelitis, or peripheral or cranial
neuropathy

Renal Persistent proteinuria (> 0.5 g Urinary creatinine (or 24-hour urinary Proteinuria > 0.5 g in 24 hours
in 24 hours or > 3+ on urine protein) > 500 mg or red blood cell casts (4);​renal biopsy class II or V lupus
dipstick testing) or cellular nephritis (8);​renal biopsy class III or
casts IV lupus nephritis (10)

ACR = American College of Rheumatology;​anti-dsDNA = anti–double-stranded DNA;​EULAR = European League Against Rheumatism;​
SLICC = Systemic Lupus International Collaborating Clinics.
*—ACR criteria have a sensitivity of 82.8% and a specificity of 93.4%;​at least four of 11 criteria required for classification.
†—SLICC criteria have a sensitivity of 96.7% and a specificity of 83.7%;​at least four of 13 criteria, including at least one clinical criterion and one
immunologic criterion, are required for classification, or the patient must have had lupus nephritis confirmed by biopsy with a positive antinuclear
or anti-dsDNA antibodies test result.
‡—EULAR/ACR criteria have a sensitivity of 96.1% and a specificity of 93.4%;​a weighted score of 10 or more criteria is required for classification. The
numbers in parentheses are the weighted score and should be added together to reach a total score.
Information from references 3, 7, and 8.

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 SYSTEMIC LUPUS ERYTHEMATOSUS

These weighted criteria are clinical (e.g., consti-

FIGURE 1 tutional, hematologic, neuropsychiatric, muco-
cutaneous, serosal, musculoskeletal, renal) and
Patient has symptoms from multiple organ systems: cardiovascular, con-
stitutional, gastrointestinal, hematologic, integumentary, musculoskeletal,
immunologic (i.e., antiphospholipid antibodies,
neuropsychiatric, pulmonary, renal, reproductive, reticuloendothelial (Table 1) complement proteins, and SLE-specific antibod-
ies).7 A diagnosis of SLE is made in consultation
with a rheumatologist. Table 1 summarizes the
Suspect SLE
classification criteria of SLE.3,7,8
Figure 1 presents an algorithm for the diagno-
Obtain antinuclear antibody titer sis of SLE in the primary care setting.7,9

Diagnosis
CLINICAL PRESENTATION
Negative: very low Positive (i.e., antinuclear antibody titer of 1:80 or more):
Patients with SLE commonly present to their
probability of SLE complete blood count with differential, urinalysis, ​anti-
dsDNA, anti-Smith, and anticardiolipin antibodies family physicians with multiple nonspecific
symptoms, making it difficult to diagnose. Lab-
oratory testing may be negative early in the onset
of SLE. Fatigue is the most prevalent symptom
Meets a weighted score of 10 or more in the follow-
SLE unlikely and is nonspecific but may be associated with
if no organ
ing 2019 European League Against Rheumatism/
involvement or
weight loss, fever without a source of infection,
American College of Rheumatology criteria:
typical laboratory and joint pain.10 Malar rash (31%;​Figure 2), pho-
Clinical: findings tosensitivity with associated acute and subacute
Acute cutaneous lupus (6); acute pericarditis (6);
autoimmune hemolysis (4); delirium (2); fever (2);
cutaneous lupus rash (23%;​Figure 39), pleuritic
joint involvement (6); leukopenia (3); nonscarring chest pain (16%), Raynaud phenomenon (16%),
alopecia (2); oral ulcers (2); pleural/pericardial effu- and mouth sores (12.5%) are less common.11 The
sion (5); proteinuria > 0.5 g in 24 hours (4); psychosis
(3); renal biopsy class II or V lupus nephritis (8); renal
differential diagnosis for SLE is summarized in
biopsy class III or IV lupus nephritis (10); seizure (5); Table 2.12
subacute cutaneous or discoid lupus (4); thrombo-
cytopenia (4)
INITIAL EVALUATION
Immunologic:
Anticardiolipin immunoglobulin G antibodies
SLE should be considered in patients who pres-
or anti-beta2-glycoprotein 1 antibodies or lupus ent with symptoms involving multiple organ
anticoagulant (2); low C3 or low C4 levels (3); low systems after ruling out infectious causes. In
C3 and low C4 levels (4); anti-dsDNA or anti-Smith
antibodies (6)
addition to constitutional symptoms, the cardio-
vascular, gastrointestinal, hematologic, integ-
umentary, musculoskeletal, neuropsychiatric,
Diagnose SLE pulmonary, renal, and reproductive systems are
most often affected.8 The reticuloendothelial sys-
Anti-dsDNA = anti–double-stranded DNA;​SLE = systemic lupus tem involving the phagocytic function of macro-
erythematosus.
phages and monocytes also may be affected.
When SLE is clinically suspected, the diagnos-
Algorithm for the diagnosis of SLE in the primary care setting. tic workup should collect information that allows
Adapted with permission from Lam NCV, Ghetu MV, Bieniek ML. Systemic lupus appropriate use of new classification criteria. The
erythematosus:​primary care approach to diagnosis and management. Am Fam EULAR/ACR classification system helps classify
Physician. 2016;​94(4):​287, with additional information from reference 7.
SLE based on a combination of physical find-
ings and laboratory criteria. The clinician should
obtain an initial ANA titer. ANA is not spe-
The EULAR/ACR criteria have a sensitivity of 96% and an cific but highly sensitive in about 95% of patients.13 SLE is
increased specificity of 93%. In these criteria, points are uncommon in patients with a negative ANA titer. A positive
given for each clinical and immunologic criterion met. If ANA titer may occur in conditions such as systemic scle-
the ANA titer is positive, the criteria are additively weighted rosis, diabetes mellitus, viral infections, and autoimmune
from 2 to 10, with a score of 10 required for classification. thyroid disease.14,15

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 SYSTEMIC LUPUS ERYTHEMATOSUS

In patients with a positive ANA titer, specific laboratory

FIGURE 2 tests should include anti-dsDNA, anti-Smith, anti-ribonu-
cleoprotein, anticardiolipin, anti-beta 2-glycoprotein 1, and
lupus anticoagulants, all of which can be applied to the
classification system.12 Urinalysis, comprehensive meta-
bolic panel, complete blood count, and a direct Coombs test
should be obtained with the initial evaluation. Erythrocyte
sedimentation rate and C-reactive protein levels are useful
in quantifying the disease activity.16
Depending on the results of the initial evaluation, fur-
ther testing may include skin, kidney, muscle, or nerve
biopsy. A kidney biopsy is recommended by the ACR for
patients with evidence of active lupus nephritis, helping to
classify the disease.17 Use of magnetic resonance imaging,
computed tomography, ultrasonography, or other testing
may be indicated. These results help identify existing con-
ditions that may lead to disease flare-ups and complications
and influence the treatment plan. For example, individuals
with a history of seizures would require magnetic resonance
imaging of the brain and electroencephalography for fur-
ther workup, or patients with cognitive impairment would
have a neuropsychological evaluation by a psychologist to
establish a baseline.18

Assessment of Severity
Malar rash. A disease flare-up consists of a measurable increase in dis-
ease activity, usually leading to a change in treatment.19 Some

FIGURE 3

A B

Subacute cutaneous lupus rash on the (A) neck and (B) back.
Reprinted with permission from Lam NCV, Ghetu MV, Bieniek ML. Systemic lupus erythematosus:​primary care approach to diagnosis and man-
agement. Am Fam Physician. 2016;​94(4):​289.

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 SYSTEMIC LUPUS ERYTHEMATOSUS
TABLE 2

Differential Diagnosis of Systemic Lupus Erythematosus

Differential diagnosis Distinguishing features Diagnostic approach

Adult-onset Still Arthralgia, fever, lymphadenopathy, Elevated erythrocyte sedimentation rate, elevated ferritin level,
disease splenomegaly leukocytosis, and anemia

Behçet syndrome Aphthous ulcers, arthralgia, uveitis Recurrent oral ulcers plus two of the following:​eye lesions,
genital ulcers, skin lesions

Chronic fatigue Persistent and unexplained fatigue that Perform the following tests to rule out other diseases:​com-
syndrome significantly impairs daily activities plete blood count, erythrocyte sedimentation rate, C-reactive
protein level, complete metabolic panel, thyroid-stimulating
hormone, urinalysis

Endocarditis Arterial emboli, arthralgia, fever, heart mur- Positive echocardiography findings with vegetation on heart
mur, myalgia valve;​positive blood culture

Fibromyalgia Poorly localized musculoskeletal pain with Digital palpation of soft tissue tender points:​gluteal, greater
hyperalgesia and allodynia trochanter, knee, lateral epicondyle, low cervical, occiput,
second rib, supraspinatus, trapezius

HIV infection Arthralgia, fever, lymphadenopathy, malaise, Western blot assay for detection of HIV antibodies
myalgia, peripheral neuropathy, rash

Inflammatory bowel Diarrhea, peripheral arthritis, rectal bleed- Perform colonoscopy to assess disease activity;​measure
disease ing, tenesmus C-reactive protein level, platelets, and erythrocyte sedimenta-
tion rate;​test for anemia

Lyme disease Arthritis, carditis, erythema migrans, neuritis Perform serologic testing for Lyme disease

Mixed connective Arthralgia, myalgia, puffy fingers, Raynaud Elevated erythrocyte sedimentation rate and hypergamma-
tissue disease phenomenon, sclerodactyly globulinemia;​positive anti-U1RNP antibodies

Psoriatic arthritis Psoriasis before or after joint disease, nail Inflammatory articular disease and more than three of the
changes in fingers and toes following:​dactylitis, nail changes, negative rheumatoid factor,
psoriasis, radiographic evidence of new bone formation in
hand or foot

Reactive arthritis Acute nonpurulent arthritis from infection Clinical diagnosis to identify triggers;​serologic findings of
elsewhere in the body;​evaluate for infec- recent infections may be present
tious urethritis or colitis

Rheumatoid arthritis Morning joint stiffness lasting more than Positive test results for rheumatoid factor and anti-cyclic
one hour;​affected joints are usually sym- citrullinated antibodies;​synovial fluid reflects inflammatory
metrical, tender, and swollen state

Sarcoidosis Cough, dyspnea, fatigue, fever, night Perform chest radiography;​bilateral adenopathy with
sweats, rash, uveitis biopsy revealing noncaseating granuloma;​elevated
angiotensin-converting enzyme level

Systemic sclerosis Arthralgia, decreased joint mobility, myalgia, Perform tests for specific autoantibodies
Raynaud phenomenon, skin induration

Thyroid disease Dry skin, fatigue, feeling cold, weakness Measure thyroid-stimulating hormone

Information from reference 12.

circumstances that increase disease flare-ups include sunlight SLEDAI-2K score of 6 or less, moderate disease has a score
exposure, hormonal changes, infection, and medications. of 7 to 12, and severe disease has a score of more than 12.19
There are multiple tools to assess disease severity, but
the Systemic Lupus Erythematosus Disease Activity Index Management
2000 (SLEDAI-2K) is the most commonly used. The tool GOALS OF TREATMENT
is available online at https://​www.​mdcalc.​com/​calc/​10099/​ Management of SLE is directed at achieving complete
systemic-​lupus-​erythematosus-​disease-​activity-​index-2000- remission or low disease activity, minimizing the use of glu-
sledai-2k. cocorticoids, preventing flare-ups, and improving quality of
A disease flare-up is classified as mild, moderate, or severe life.19,22,23 Complete remission is defined as the absence of
depending on the disease activity.20,21 Mild disease has a clinical activity (i.e., a SLEDAI-2K score of 0) with no use

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 SYSTEMIC LUPUS ERYTHEMATOSUS

of glucocorticoid or immunosuppressive therapy.24 Low dis- patients to taper and eventually discontinue glucocorti-
ease activity is a SLEDAI-2K score of 3 or less while on anti- coids. High-dose intravenous methylprednisolone (usually
malarials (e.g., hydroxychloroquine),
or a SLEDAI-2K score of 4 or less while
TABLE 3
taking no more than 7.5 mg per day of
prednisone and well-tolerated immu- Medications Used to Treat Systemic Lupus Erythematosus
nosuppressive agents.25 Therapies
are typically managed by or co-man- Medication Indication Dosage
aged with experts in rheumatology. First-line treatment
Management in severe disease may Glucocorticoids Low dose for treating Low dose:​ ≤ 7.5 mg of prednisone
require a multidisciplinary approach.19 SLE without major organ per day
damage;​high dose for
Table 3 lists medications used to treat High dose:​40 to 60 mg of predni-
cerebritis, lupus nephritis,
SLE. 8,17,26-28
refractory conditions, and
sone per day

thrombocytopenia
PHARMACOTHERAPY Hydroxychloroquine Recommended for all 5 mg per kg of body weight per
Hydroxychloroquine. Hydroxychloro- patients with SLE;​long- day (200 to 400 mg per day)
quine is recommended for all patients term protective effect on
SLE-related organ damage
with SLE because it prevents flare-ups,
organ damage, and thrombosis and
Nonsteroidal Lupus joint pain Depends on preparation
increases long-term survival.19,29 It anti-inflammatory
has a long half-life and may take two drugs
to eight weeks to be effective. Retinal
Second-line treatment
toxicity is the main adverse effect.
Azathioprine Lupus nephritis, severe SLE 1.5 to 2.5 mg per kg per day
Based on existing evidence that shows
the risk of toxicity is very low for doses
below 5 mg per kg of body weight, the Methotrexate Arthritis, cutaneous lupus, 7.5 to 25 mg per week
daily dosage should not exceed this serositis, severe SLE
threshold.19 Risk factors for retinal
toxicity include longer duration of use, Third-line treatment
higher dosage, preexisting retinal or Anifrolumab Moderate and severe SLE, 300 mg every four weeks adminis-
macular disease, older age, concomi- (Saphnelo) lupus nephritis tered via intravenous infusion
tant use of tamoxifen, and kidney and
liver disease.19,30 Baseline funduscopic Belimumab SLE 10 mg per kg per intravenous dose
examination, visual field testing, and (Benlysta) 200 mg subcutaneously once per
spectral-domain optical coherence week
tomography should be performed to Cyclophosphamide Lupus nephritis, severe SLE 500 to 1,000 mg per m2 intrave-
rule out preexisting maculopathy at nously once per month

the time of initiation. Annual screen-

Mycophenolate Lupus nephritis, refractory 2 to 3 g per day
ing should be performed in those at
mofetil SLE
high risk but can be deferred to five
Rituximab (Rituxan) Refractory severe SLE One-time administration of two
years in low-risk patients.29,31 1-g doses intravenously, two
Glucocorticoids. Glucocorticoids weeks apart
provide rapid symptom relief in acute Voclosporin Lupus nephritis 23.7 mg orally every 12 hours
disease and during flare-ups. Pro- (Lupkynis)
longed glucocorticoid use can have
detrimental effects, including irrevers- SLE = systemic lupus erythematosus.
ible organ damage. The aim should be *—Estimated lowest GoodRx price for one month’s treatment unless otherwise noted. Actual cost
to minimize the daily dosage of pred- will vary with insurance and by region. Generic price listed first;​brand name price in parentheses.
nisone to 7.5 mg or less or discontinue Information obtained at https://​w ww.goodrx.com (accessed January 26, 2023;​zip code:​66211).
glucocorticoids.32 Early initiation Information from references 8, 17, and 26-28.
of immunosuppressive agents helps

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 SYSTEMIC LUPUS ERYTHEMATOSUS

250 to 1,000 mg per day for three days) may be used in acute, Immunosuppressive Therapy. The choice of agent depends
organ-threatening disease or during severe flare-ups.33 on disease manifestations, patient age, childbearing poten-
tial, safety concerns, and cost.19 Meth-
otrexate and azathioprine may be
considered if a trial of hydroxychlo-
roquine fails to manage the disease
or glucocorticoids cannot be tapered
Monitoring and precautions Cost* off. Mycophenolate mofetil is a potent
immunosuppressant with effective-
Glucose levels every three to six months and total cholesterol $5 (—) for 30 10-mg ness in renal and nonrenal lupus.34,35
and bone density testing annually;​use with caution in patients prednisone tablets;​ Cyclophosphamide may be used in
with hyperlipidemia, hypertension, hyperglycemia, infection, or $7 (—) for 60 20-mg organ-threatening disease, especially
osteoporosis prednisone tablets affecting the renal, cardiopulmonary,
or neuropsychiatric systems.
Baseline funduscopic examination, visual field testing, and $6 (—) for 30 200-mg Biologic Agents. Belimumab (Ben-
spectral-domain optical coherence tomography should be tablets lysta), a B lymphocyte stimulating fac-
performed at the time of initiation;​annual screening is per- tor, is used in SLE and lupus nephritis
formed in those at high risk but can be deferred to every five
years in low-risk patients at the time of initiation, then annually
when first-line treatments provide
inadequate control. Patients more
Complete blood count and renal testing annually;​use with Depends on
caution in patients with gastrointestinal bleeding, liver or kidney preparation likely to respond are those with high
disease, or hypertension disease activity, who are taking a pred-
nisone dosage of more than 7.5 mg per
day, and with serologic activity (low
Complete blood count and metabolic panel at least every three $15 (—) for 60 50-mg
months to monitor for hepatotoxicity, lymphoproliferative tablets
C3/C4, high anti-dsDNA antibody
disorders, and myelosuppression titers).36,37
Complete blood count and metabolic panel at least every three $3 (—) for 12 2.5-mg Several open-label trials and reg-
months to monitor for hepatic fibrosis or myelosuppression;​ tablets istry studies have found that ritux-
additional monitoring for fibrosis and pulmonary infiltrates imab (Rituxan) is effective in SLE
that is resistant to standard treatment.
Monitor for respiratory tract infections and hypersensitivity Only administered Because of insufficient evidence from
by a health care randomized controlled trials, ritux-
professional imab is currently used off-label in
Monitor for serious infection and malignancies Only available at spe- patients with severe renal, hemato-
cialty pharmacies logic, and neuropsychiatric disease;​
in patients with SLE that has been
Complete blood count and metabolic panel at least every three Only administered resistant to other immunosuppres-
months to monitor for hemorrhagic cystitis, immunosuppres- by a health care sive agents and/or belimumab;​or in
sion, malignancy, and myelosuppression professional
patients for whom other therapeutic
Complete blood count and metabolic panel at least every three $30 (—) for 240
options are contraindicated. More
months to monitor for infection and myelosuppression 250-mg capsules
than one immunosuppressive drug
Complete blood count every two to four months;​use with Only available at spe-
caution in patients with a history of infusion reaction cialty pharmacies
needs to have been ineffective before
administering rituximab.38,39
Establish baseline estimated glomerular filtration rate prior to Only available at spe- Voclosporin (Lupkynis) is an oral
initiating, then every two weeks for the first month and every cialty pharmacies calcineurin inhibitor immunosuppres-
four weeks thereafter;​monitor blood pressure every two weeks sant approved by the U.S. Food and
Drug Administration in 2021 for the
treatment of lupus nephritis in com-
bination with mycophenolate mofetil
and glucocorticoids.27 Anifrolumab
(Saphnelo) is an immunoglobu-
lin gamma 1 kappa monoclonal

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 SYSTEMIC LUPUS ERYTHEMATOSUS

antibody antagonist of the type 1 interferon receptor and mofetil and cyclophosphamide are the immunosup-
was approved by the U.S. Food and Drug Administration in pressive agents of choice for induction therapy for lupus
2021 for the treatment of moderate and severe SLE.28 nephritis. Mycophenolate mofetil or azathioprine may
be used for maintenance therapy. Management of spe-
SPECIFIC ORGAN SYSTEM COMPLICATIONS cific organ systems in patients with SLE is summarized in
Screening for nephritis with urinalysis and serum creati- Table 4.19,40-45 Figure 4 outlines the management of nonre-
nine levels should be done at three- to six-month intervals nal SLE.19,46
in all patients with SLE. For patients with features sug-
gesting nephritis, a 24-hour urine test for protein or a spot PREGNANCY COMPLICATIONS
urine protein/creatinine ratio should be obtained.17 Refer- Pregnant patients with SLE have an increased risk of spon-
ral for renal biopsy should be considered in patients with taneous abortions, stillbirths, fetal growth restriction, and
proteinuria of at least 1 g in 24 hours or at least 0.5 g in preeclampsia.26 Pregnancy may increase disease activity
24 hours with hematuria or cellular casts. Mycophenolate and precipitate disease flare-ups.47

TABLE 4

Management of Specific Systemic Manifestations of Systemic Lupus Erythematosus

Lifetime
Organ system prevalence Treatment Prevention and screening

Cardiovascular 28% to 40% Antihypertensive agents, cholesterol-lowering agents Treat risk factors aggressively

Hematologic Most patients Thrombocytopenia: Monitor and treat infection,

First line:​glucocorticoids plus immunosuppressive therapy especially in patients with
(i.e., azathioprine, mycophenolate mofetil, or cyclosporine);​ leukopenia
intravenous methylprednisolone with or without intravenous
immunoglobulins
Refractory:​ rituximab
Autoimmune hemolytic anemia:​glucocorticoids plus immuno-
suppressive therapy

Integumentary 70% to 80% First line:​topical agents (e.g., glucocorticoids, calcineurin Use sunscreen and wear
inhibitors) and hydroxychloroquine with or without systemic protective clothing
glucocorticoids.
Refractory:​methotrexate;​other agents include retinoids, dap-
sone (Aczone), and mycophenolate mofetil

Musculoskeletal 95% First line:​nonsteroidal anti-inflammatory drugs, hydroxychloro- —

quine, glucocorticoids
Refractory:​immunosuppressive therapy such as methotrexate
or mycophenolate mofetil

Neuropsychiatric 12% to 23% Based on etiology:​ Control aggravating factors

Inflammatory:​glucocorticoids with or without immunosup- and symptoms
pressive therapy
Embolic/thrombotic/ischemic:​ anticoagulant

Pulmonary 16% Depends on type of involvement and severity;​glucocorticoids, —

azathioprine, cyclophosphamide, or mycophenolate mofetil;​
plasmapheresis

Renal 50% Induction:​mycophenolate mofetil or cyclophosphamide Urinalysis and serum creati-

Maintenance:​mycophenolate mofetil or azathioprine nine test every one to three
months

Information from references 19 and 40-45.

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 SYSTEMIC LUPUS ERYTHEMATOSUS

FIGURE 4

Nonrenal SLE

Mild: SLEDAI-2K Moderate: SLEDAI-2K Severe: SLEDAI-2K

score of ≤ 6 score of 7 to 12 score of > 12

First line: hydroxychloroquine, First line: hydroxychloroquine, and if needed, add First line: hydroxychloroquine, and if
glucocorticoids (orally or glucocorticoids (orally or intravenously), methotrexate, needed, add glucocorticoids (orally or
intramuscularly) azathioprine, calcineurin inhibitors, or mycophenolate intravenously), mycophenolate mofetil,
Refractory: add methotrexate mofetil or cyclophosphamide
Refractory: add belimumab (Benlysta) Refractory: add rituximab (Rituxan)

Target
Remission: SLEDAI-2K score = 0, hydroxychloroquine,
no glucocorticoids
Low disease activity: SLEDAI-2K score of ≤ 4, hydroxy-
chloroquine, prednisone dosage of ≤ 7.5 mg per day
(in stable dosages and if well-tolerated)

SLE = systemic lupus erythematosus;​SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000.

Algorithm for the management of nonrenal SLE.

Information from references 19 and 46.

Active disease six months before pregnancy, lupus Patients should be closely monitored throughout preg-
nephritis, and discontinuation of antimalarial agents are nancy to detect and manage complications or flare-ups.
risk factors for adverse maternal outcomes.29 Preconception Patients with SLE and antiphospholipid syndrome may need
counseling regarding risks, planning the timing of preg- additional anticoagulant agents throughout pregnancy and
nancy, and using a multidisciplinary approach play a major in the postpartum period.
role in the management of SLE in patients contemplating Other than a consultation with a physician specializing
pregnancy. in maternal-fetal medicine and a rheumatologist, the eval-
Hydroxychloroquine should be continued during preg- uation should include an assessment of antiphospholipid
nancy because it has been shown to control disease activ- antibodies and anti-Ro/SS-A and anti-La/SS-B antibodies.
ity. It may reduce pregnancy complications, including Anti-Ro and anti-La antibodies may be present in patients
preeclampsia and cardiac neonatal lupus.47-50 Prednisone, with SLE and can be cardiotoxic to the fetus. Varying
azathioprine, and tacrolimus may be used in pregnancy if degrees of congenital heart block can be seen in 1% to 3%
benefits outweigh risks, whereas methotrexate, mycopheno- of children born to patients who are seropositive.52 Heart
late mofetil, cyclophosphamide, and leflunomide are con- block can be incomplete or complete, leading to heart fail-
traindicated in pregnancy. Mycophenolate mofetil is highly ure in utero and hydrops fetalis. For patients with anti-Ro
teratogenic and should be discontinued at least six weeks and anti-La antibodies, fetal echocardiography should be
before conceiving. These patients can be switched to aza- performed multiple times from 16 through 26 weeks of
thioprine and/or tacrolimus at least three months before gestation; this period is when the fetus has the highest risk
conception to help decrease disease activity. According to for onset of congenital heart block.29 There is no known
the U.S. Preventive Services Task Force, low-dose aspirin effective therapy for complete heart block, but incomplete
should be initiated in pregnant patients with an increased heart block is often treated with dexamethasone because
risk of preeclampsia after 12 weeks of gestation.51 it can cross the placenta. Hydroxychloroquine use during

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 SYSTEMIC LUPUS ERYTHEMATOSUS

SORT:​KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating Comments

Treatment of systemic lupus erythematosus should aim for complete remis- C Expert opinion and consensus guideline
sion or low disease activity and prevention of flare-ups in all organs using the
lowest possible dose of glucocorticoids.19,22,23

Hydroxychloroquine is recommended for all patients with systemic lupus C Consensus guideline based on inconsis-
erythematosus.19,29 tent or limited-quality patient-oriented
evidence

Hydroxychloroquine should be continued during pregnancy because it has B Inconsistent or limited-quality

been shown to control disease activity. It may reduce pregnancy complica- patient-oriented evidence and expert
tions, including preeclampsia and cardiac neonatal lupus.47-50 opinion

Patients with active disease should be evaluated at least every one to three C Expert opinion and consensus guideline
months, and measurements of blood pressure, anti–double-stranded DNA
antibodies, and complement and C-reactive protein levels;​urinalysis;​com-
plete blood count;​and kidney and liver function tests should be performed.46

A = consistent, good-quality patient-oriented evidence;​B = inconsistent or limited-quality patient-oriented evidence;​C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://​w ww.aafp.
org/afpsort.

pregnancy is associated with a reduced risk of fetal develop- Patients with chronic kidney disease should receive
ment of cardiac neonatal lupus.49 one dose of pneumococcal conjugate vaccine (PCV20 or
PCV15). When PCV15 is used, it should be followed by a
CONTRACEPTION dose of pneumococcal polysaccharide vaccine (PPSV23).54
Patients with SLE can use most contraceptive methods, Live vaccines should not be given to patients with SLE when
preferably long-acting reversible contraception such as they are receiving immunosuppressive therapy and should
intrauterine devices. Those with antiphospholipid syn- be delayed for at least one month after completion of therapy.
drome should not use estrogen-containing contraceptives Management of modifiable risk factors, including hyper-
because of increased risk of thrombosis.53 tension, dyslipidemia, diabetes, high body mass index, and
smoking, should be reviewed at baseline and at least annu-
Monitoring ally. Immunosuppressive therapy may lead to toxicities.
SLE has wide-ranging effects on physical, psychological, Close monitoring of medications by regular laboratory test-
and social well-being that impact quality of life. All patients ing and clinical assessment should be performed in accor-
with SLE should receive ongoing education, counseling, dance with drug monitoring guidelines.46
and support. Those with mild SLE can be monitored by pri- Table 5 describes recommendations for follow-up and
mary care physicians in conjunction with rheumatology.8 monitoring for complications related to SLE.8,17,46,55-57
Patients with increased disease activity, complications, or
This article updates previous articles on this topic by Lam, et al.9;​
adverse effects from treatment should be managed by a Gill, et al.58;​and Petri.59
rheumatologist.8 Family physicians can assist the rheuma-
Data Sources:​Dynamed, PubMed, Cochrane Database of System-
tologist in monitoring disease activity and providing phar-
atic Reviews, Essential Evidence Plus, including POEMs, the U.S.
macotherapy in patients with moderate to severe SLE. Those Preventive Services Task Force, and the Centers for Disease Con-
with active disease should be evaluated at least every one to trol and Prevention vaccine guidelines were searched using key
three months, and measurements of blood pressure, anti- words systemic lupus erythematosus, lupus nephritis, SLE diag-
dsDNA antibodies, complement and C-reactive protein lev- nosis, and SLICC. The American College of Rheumatology, the
British Society for Rheumatology guideline for the management
els;​urinalysis;​complete blood count;​and kidney and liver
of systemic lupus erythematosus in adults, and the American Col-
function tests should be performed. Patients with stable low lege of Obstetricians and Gynecologists practice guidelines were
disease activity or who are in remission can be evaluated also searched. We used references from the previous AFP articles
less often.46 on this topic. Search dates:​April and May 2022, and January 2023.

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 SYSTEMIC LUPUS ERYTHEMATOSUS

TABLE 5

Follow-up, Monitoring, and Management for Selected Complications of Systemic Lupus

Erythematosus
Complications Frequency of follow-up Prevention, monitoring, and management

None;​mild, sta- Every three to six months History for features of systemic lupus erythematosus, physical
ble systemic lupus examination, complete blood count, creatinine level, urinalysis, anti–
erythematosus double-stranded DNA antibodies, complement levels;​keep all health
maintenance screenings and vaccinations up to date

Moderate to severe Frequent Monitor as recommended by rheumatologist and lupus care specialists
systemic lupus ery-
thematosus with
complications

Systems monitoring
Cardiovascular Every visit Optimal lupus control with minimal glucocorticoid use;​judicious use of
abnormalities antimalarial and other immunosuppressive agents;​smoking cessation,
adequate exercise, low-cholesterol diet, lipid-lowering therapy, blood
pressure control, screening for diabetes mellitus
Hematology:​ severe Weekly Hematocrit and reticulocyte count;​may require transfusion
hemolytic anemia
Hematology:​ severe Weekly Platelet count weekly initially;​may require transfusion
thrombocytopenia
(< 50,000 cells per mm3)
Infection Every visit Ensure that vaccinations are up to date;​judicious use of immunosuppres-
sive agents
Malignancy Yearly Ensure that routine cancer screenings are up to date;​screen for high-risk
cancers as indicated (e.g., hematologic, non-Hodgkin lymphoma, lung,
cervical)
Renal abnormalities Every three months or more Regular screening for proteinuria and hematuria;​regular serum creatinine
frequently, depending on level;​patients with chronic kidney disease should receive pneumococcal
disease state vaccination;​new-onset nephritis needs more frequent monitoring

Medication monitoring
Hydroxychloroquine Annual vision screening is Baseline funduscopic examination, visual field testing, and spectral-
performed in those at high domain optical coherence tomography should be performed at the time
risk but can be deferred of initiation
to five years in low-risk
patients at the time of initi-
ation, then annually
Low-dose Every visit to every one to Keep dosage as low as possible;​healthy diet with adequate physical activ-
glucocorticoids two years ity;​smoking cessation;​annual cholesterol and glucose testing;​consider
dual-energy x-ray absorptiometry every one to two years for patients
receiving long-term therapy
High-dose glucocorti- Every visit Pursue steroid-sparing agent;​use lowest dose possible to achieve
coids (e.g., prednisone, optimum disease control;​glucose testing every three to six months;​
> 30 mg​per day) cholesterol testing annually;​dual-energy x-ray absorptiometry every one
to two years;​maintain high index of suspicion for avascular necrosis if
patient has acute joint pain
Immunosuppressive or Every one to two weeks Complete blood count and liver function testing at baseline, then every
cytotoxic agents initially, then every one to one to two weeks at initiation of therapy, then one to three months;​
three months judicious use of immunosuppressive agents, vigilance for signs and symp-
toms of infection;​routine cancer screening;​avoidance of live vaccines;​
if live vaccines are needed, administer one month after completion of
therapy

Information from references 8, 17, 46, and 55-57.

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 SYSTEMIC LUPUS ERYTHEMATOSUS

14. Sherer Y, Gorstein A, Fritzler MJ, et al. Autoantibody explosion in sys-

The Authors temic lupus erythematosus:​more than 100 different antibodies found
in SLE patients. Semin Arthritis Rheum. 2004;​3 4(2):​501-537.
NGUYET-CAM V. LAM, MD, FAAFP, is the program director of 15. Goldblatt F, O’Neill SG. Clinical aspects of autoimmune rheumatic dis-
St. Luke’s Bethlehem (Pa.) Family Medicine Residency at St. eases. Lancet. 2013;​382(9894):​797-808.
Luke’s University Hospital. 16. Narain S, Richards HB, Satoh M, et al. Diagnostic accuracy for lupus and
other systemic autoimmune diseases in the community setting. Arch
JUDY ABU BROWN, MD, is a clinical faculty member at St. Intern Med. 2004;​164(22):​2435-2441.
Luke’s Bethlehem Family Medicine Residency at St. Luke’s 17. Hahn BH, McMahon MA, Wilkinson A, et al.;​American College of Rheu-
University Hospital. matology. American College of Rheumatology guidelines for screen-
ing, treatment, and management of lupus nephritis. Arthritis Care Res
RICHA SHARMA, MD, is a clinical faculty member at St. Luke’s (Hoboken). 2012;​6 4(6):​797-808.
Bethlehem Family Medicine Residency at St. Luke’s University 18. Bertsias GK, Ioannidis JPA, Aringer M, et al. EULAR recommendations
Hospital. for the management of systemic lupus erythematosus with neuropsy-
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Address correspondence to Nguyet-Cam V. Lam, MD, FAAFP, committee for clinical affairs. Ann Rheum Dis. 2010;​69(12):​2074-2082.
St. Luke’s Hospital, 2830 Easton Ave., Bethlehem, PA 18017
19. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the
(email:​nguyet-cam.lam@​sluhn.org). Reprints are not available EULAR recommendations for the management of systemic lupus ery-
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