English - Systemic Lupus Erythematosus - ClinicalKey

3/27/23, 12:14 AM Systemic Lupus Erythematosus - ClinicalKey
CLINICAL OVERVIEW
Systemic Lupus Erythematosus
Elsevier Point of Care (see details)
Updated March 14, 2023. Copyright Elsevier BV. All rights reserved.
Synopsis
Urgent Action
Patients with severe life- or organ-threatening manifestations require admission to
hospital; treatment with high-dose glucocorticoids, alone or in combination with
cytotoxic-immunosuppressive drugs, may be required 1 2
Key Points
Systemic lupus erythematosus is a chronic, multisystem autoimmune disease characterized
by production of a variety of autoantibodies and by complement consumption
Patients typically present with constitutional symptoms (eg, fever, fatigue, weight loss),
arthralgias, mucocutaneous symptoms (eg, malar rash, oral ulceration, alopecia), and/or
cytopenias; less commonly, patients present with serious renal, neuropsychiatric, or
cardiopulmonary disease
Diagnosis should be suspected in a female of childbearing age presenting with a classic

constellation of clinical and laboratory findings. However, it may be overlooked initially in
patients presenting with single-organ involvement, becoming evident only with
development of additional disease features
There is no definitive diagnostic laboratory test; however, positive immunologic test results
support the diagnosis. The presence of positive antinuclear antibodies—in conjunction with
anti-dsDNA antibodies, low complement levels, or anti-Sm antibodies—is highly suggestive
of systemic lupus erythematosus in patients with suspicious clinical findings
Systemic lupus erythematosus classification criteria are useful to confirm clinical judgment;
however, these criteria are not specifically designed or validated for the purpose of
https://www.clinicalkey.com/#!/content/clinical_overview/67-s2.0-6eb7df84-9374-4f7d-b8e0-06152919f9e6 1/52
diagnosing systemic lupus erythematosus
Hydroxychloroquine, an antimalarial and antirheumatic immunomodulator, is the

cornerstone of treatment for all patients with systemic lupus erythematosus. It should be
started at diagnosis and should be continued in long term
Additional pharmacotherapy is individualized according to clinical manifestations, specific

organ involvement, disease activity and severity, comorbidities, and therapeutic response
Glucocorticoids are prescribed for disease flares, with a goal of discontinuation. If

maintenance steroids are required, aim for the lowest dose possible (6 mg/day or less)
Cytotoxic-immunosuppressive agents (eg, methotrexate, azathioprine, mycophenolate,

cyclophosphamide) are added for control of more severe disease and as steroid-sparing
agents
Biologic agents belimumab and rituximab may be considered for refractory disease
Comorbidities associated with systemic lupus erythematosus include antiphospholipid

syndrome, accelerated atherosclerosis, fibromyalgia, and treatment-related decreased bone
mineral density
Nonpharmacologic measures (eg, sun protection), reducing cardiovascular risk, and

preventing osteoporosis are important in disease management 1
Systemic lupus erythematosus is associated with increased mortality. Early deaths are
usually related to disease activity and infections, whereas later deaths are primarily
associated with cumulative organ damage, atherosclerotic cardiovascular disease, or
treatment-related complications
Pitfalls
Diagnosis may be challenging owing to diverse manifestations and a wide range of
differential diagnoses
Basing diagnosis on systemic lupus erythematosus classification criteria alone may result in
underdiagnosis and undertreatment because patients may have the disease without fulfilling
these criteria; use clinical judgment and refer patients with uncertain diagnosis to a
rheumatologist who has experience treating systemic lupus erythematosus
Before attributing fever to systemic lupus erythematosus disease activity, consider

underlying infection or drugs as a cause, particularly in immunosuppressed patients
Type 2 (noninflammatory) symptoms, such as fatigue, diffuse pain, sleep disturbance, and
brain fog, will not respond to glucocorticoids; avoid chasing these symptoms with
increasing doses
Comorbidities such as fibromyalgia are common and overlapping manifestations (eg, pain,
fatigue) may confound decision making; avoid treating nonlupus manifestations with lupus
drugs
Terminology
Clinical Clarification
Systemic lupus erythematosus is a chronic, multisystem autoimmune disease characterized
by production of autoantibodies and by complement consumption
Clinical manifestations are highly variable and range from mild to life-threatening. Disease
can involve any organ system but commonly affects skin, joints, serosal membranes,
hematologic system, and kidneys. Antiphospholipid syndrome with thromboses and/or
adverse pregnancy outcomes occurs in a subset of patients
Classification
Classification criteria published by rheumatologic organizations
Designed primarily to create homogeneous cohorts for clinical research; 4 however,

widely used as a diagnostic framework to confirm clinical judgment 3
Most recent classification criteria are as follows:
2019 European League Against Rheumatism/American College of Rheumatology

classification criteria for systemic lupus erythematosus 5
Weighted multicriteria system, with a positive antinuclear antibodies titer (1:80 or

higher) at any time as a required entry criterion
Points are accumulated from clinical findings (ie, constitutional, hematologic,

neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and immunologic
abnormalities (ie, antibodies specific to systemic lupus erythematosus, low
complement protein levels, antiphospholipid antibodies)
Patients accumulating 10 or more points are classified
SLICC (Systemic Lupus International Collaborating Clinics) criteria of 2012 6
Case must satisfy at least 4 criteria, including at least 1 of 11 clinical criteria and 1 of
6 immunologic criteria, or the patient must have biopsy-proven lupus nephritis in
the presence of antinuclear antibodies or anti-dsDNA (double-stranded DNA)

antibodies
Categorization of lupus and lupus-related disorders based on phenotype
Systemic lupus erythematosus
Multisystemic involvement of skin, joints, serosal membranes, hematologic system,

kidneys, central nervous system, vasculature, heart, or lungs. Chronic cutaneous (ie,
discoid) lupus may be a feature
Chronic cutaneous lupus erythematosus
Most common subtype is discoid lupus erythematosus, which can occur either in the
context of systemic lupus erythematosus or as an isolated process limited to the skin.
Characterized by coin-shaped indurated erythematous plaques, usually involving scalp,
face, and neck 7
Drug-induced lupus erythematosus
Lupuslike syndrome that develops in temporal relation to drug exposure and usually
resolves after cessation of the drug. May resemble systemic lupus erythematosus or be
limited to subacute cutaneous manifestations 7
More than 80 associated drugs have been identified. Well-known association with
hydralazine and procainamide. Other associated drugs include isoniazid, calcium
channel blockers, terbinafine, thiazide diuretics, minocycline, proton pump inhibitors,
interferons, and tumor necrosis factor α inhibitors 7
Neonatal lupus
Passive transfer of certain autoantibodies (anti-Ro/SS-A, anti-La/SS-B) which may be

present in females with (or without) systemic lupus erythematosus. Can induce a
neonatal syndrome which can include fetal heart block and/or photosensitive rash,
cytopenias, and hepatic manifestations in the newborn 7
Diagnosis
Clinical Presentation
History
Presentation varies widely
Patients may have only constitutional and other nonspecific symptoms early in the course
of illness, with progression to more classic symptoms later
Time lag to recognition of symptoms as systemic lupus erythematosus (months to years)

is not unusual
Clinical course varies. Patients may have chronic disease activity or periods of quiescence
interrupted by flares
Risk factors for symptomatic flare may be reported; recent exposure to UV light (risk for
both cutaneous and systemic flares), cigarette smoking (risk for cutaneous lupus flares),
ingestion of echinacea or trimethoprim-sulfamethoxazole (risk for both systemic and
cutaneous flares)
Common symptoms:
Constitutional (90%-95%) 8
Unexplained fever (after other causes, such as infections, are excluded)
Anorexia and mild weight loss
Symptoms associated with systemic lupus erythematosus but not related to

inflammation (do not respond to standard immunosuppressive therapies; have been
described as type 2 symptoms) 9
Marked fatigue, often described as disabling
Widespread or diffuse pain
Headaches
Brain fog
Sleep disturbance
Anxiety and/or depression
Mucocutaneous (80%-90%) 8
Rashes
Photosensitive rash lasting days to weeks
Occurs on sun-exposed areas, with onset a day or two after exposure
Coin-shaped lesions (discoid lupus plaques); can occur as an isolated form of lupus
without systemic manifestations, lasting months to years
Hair thinning and breakage
Oral and/or nasal ulcerations (often painless, and if so, may not be noticed by the
patient)
Arthralgias/arthritis (76%) 10
Morning stiffness of at least 30 minutes in the proximal interphalangeal, metacarpal-

phalangeal, and/or wrist joints 11
Joint pain or swelling in the hands
Serosal (50%-70%) 8
Pleuritis, manifested as pleuritic chest pain lasting more than 1 day 11

Pericarditis, manifested as substernal chest pain improved by sitting upright/bending
forward and worsened with cough and deep inspiration, lasting longer than 1 day
Renal (40%-60%) 8
Lupus nephritis may be asymptomatic (identified with urinalysis and/or spot protein
to creatinine ratio or 24-hour urine protein measurement), or less commonly, can have
a nephrotic presentation with peripheral edema
Neuropsychiatric (40%-60%) 8
Central nervous system
Difficulties with memory (may be a noninflammatory, type II symptom)
Seizures
Acute confusional state
Psychosis
Stroke (often mediated by antiphospholipid antibodies or hypertension)
Spinal cord dysfunction due to myelitis (rare)
Peripheral nervous system
Peripheral neuropathies, including small fiber neuropathy and mononeuritis

multiplex
Cranial neuropathies
Autonomic neuropathies
Hematologic
Anemia (often multifactorial) is present in 57%; may contribute to fatigue 10
Mild (asymptomatic) thrombocytopenia is present in about 50%, but if severe, may

result in bleeding 8
Leukopenia (most commonly lymphopenia; neutropenia may also be present) in up to

50%. If severe, may report recent infections 8
Vascular
Raynaud phenomenon (44%) 10
Pain and visible perfusion changes of the fingers (vasospasm) in response to cold or
emotional stress
Venous or arterial thromboembolism (suggests the possibility of antiphospholipid

antibody syndrome)
Other organ involvement can result in a wide variety of symptomatic presentations
Ocular
Dry, irritated eyes (keratoconjunctivitis sicca)
Pulmonary
Acute pneumonitis
Pulmonary hemorrhage
Interstitial lung disease
Pulmonary hypertension
Cardiac
Accelerated atherosclerosis with coronary artery disease
Myocarditis
Valvular dysfunction (often due to antiphospholipid antibodies)
Gastrointestinal
Acute pancreatitis
Dysmotility syndromes
Mesenteric and intestinal vasculitis
Hepatitis
Obstetric, often due to antiphospholipid antibody syndrome
Recurrent miscarriages
Late fetal loss
Preeclampsia
Preterm birth
Physical examination
Fever may be present
Hypertension suggests the possibility of lupus nephritis
Lymphadenopathy
Cervical, axillary, and inguinal nodes most commonly involved
Lymph nodes are soft and nontender
Splenomegaly may be present
Cutaneous manifestations specific to lupus
Acute forms (transient, nonscarring) are located on sun-exposed skin
Malar rash
Erythema (mild to intense) on malar areas bilaterally, sparing nasolabial folds
May also cover bridge of nose
Telangiectasias, papules, scale and crust, dyspigmentation, and epidermal atrophy

may be present; these are signs of skin damage but are not specific for lupus
Macular or maculopapular rash
Located in a photosensitive distribution
Common in V-area of neck and on arms
Subacute forms are typically located in sun-exposed areas of upper trunk and extensor
surfaces of upper extremities
Lesions are of 2 types
Annular lesions (often confluent) with raised, scaling, erythematous borders and
central clearing
Papulosquamous with psoriasiform or eczematous appearance
Chronic forms
Discoid lupus is the most common subtype
Most often develops on face, scalp, and ears, but it may also be distributed below the
neck
Sharply demarcated coin-shaped erythematous plaques with central scale

Induration is palpable (involves deep dermis)
Alopecia within the scalp lesions
So-called lupus hair, with irregular distribution of broken hairs, 5 to 25 mm long, along
frame of face 3
Scarring alopecia as a complication of discoid lupus lesions
Cutaneous manifestations not specific to lupus
Diffuse hair thinning due to telogen effluvium
Livedo reticularis (red-purple mottled lace-like appearance caused by vasculitis), which

may be precipitated by cold
Periungual telangiectasias
Raynaud phenomenon
Mucus membranes
Superficial oral and/or nasal mucosal ulcers
Acute oral lupus lesions are erythematous macules or petechiae which may erode or
ulcerate. Can involve the hard palate
Musculoskeletal
Arthritis
Symmetrical joint tenderness, erythema, and pain with motion, with or without
swelling
Typically involves the metacarpophalangeal, proximal interphalangeal, and wrist joints.

Less commonly, can involve the knee joints
Hand deformities (Jaccoud arthropathy)
Jaccoud arthropathy is characterized by ligament laxity and joint subluxation leading to

reversible deformities
Ulnar deviation of metacarpophalangeal joints with hyperextension of proximal

interphalangeal joints and hyperflexion of distal interphalangeal joints with hand
being deviated ulnarly at the wrist
Cardiopulmonary
Pleural friction rub may be heard (rare) if pleurisy is present
Dullness to percussion, and diminished breath sounds due to pleural or pericardial

effusion
Pericardial friction rub is rare
May be audible on auscultation over the left sternal border with patient sitting up and
leaning forward
Usually triphasic (early diastole, late diastole, systole); may be biphasic or monophasic
Neuropsychiatric
Deficits in cognitive efficiency and sustained attention may be present on

neuropsychological testing 12
Physical examination findings may reflect peripheral or cranial neuropathy or a

transverse myelitis which is longitudinally extensive (longitudinal myelitis)
Causes and Risk Factors
Causes
Etiology is unknown; however, pathogenesis is believed to be multifactorial, involving
genetic susceptibility, epigenetic changes, certain environmental triggers, altered immune
system function, and hormonal factors
Disease manifestations are mediated by production of autoantibodies and immune complex

deposition or cross-reaction with antigens in involved organs
Risk factors and/or associations
Age
Although disease can occur at any age, most patients are diagnosed between ages 15 and 44
years 10
About 10% to 20% of patients are diagnosed before age 18 years 13
Sex
Most commonly affects females, particularly during childbearing years 14
In adults, female to male ratio is approximately 9:1 10 15
In prepubertal children, female to male ratio is 4:3 16
Genetics
Genetic factors appear to play a role in pathogenesis based on the following:
High concordance of disease in monozygotic twins (11%-50%) 17
Evidence of familial susceptibility (parents and siblings have risk ratio of 11 and 23,
respectively 17) 15
High rate of positive antinuclear antibodies in children of females with systemic lupus
erythematosus 18
More than 80 genetic predispositions have been identified in genome-wide association
studies, but these generally increase the relative risk for systemic lupus erythematosus by
less than a factor of 2 19
Predisposing genes may be involved in generation of self-antigen, activation of innate

immune response, and activation of adaptive immune response 15
Ethnicity/race
More common and more severe in African American, African Caribbean, Native American,
Hispanic, and Asian populations than in White populations
Other risk factors/associations

Environmental and endogenous factors have been implicated in the pathogenesis of lupus
Strong epidemiologic evidence for the following exposures: 20
Exposure to silica dust 21
Current cigarette smoking 22 23
Past use of oral contraceptive use (relative risk 1.5) 24
Postmenopausal hormone replacement therapy (relative risk 1.9) 24
Other factors with risk associations
Early age at menarche 24
Early age at menopause 24
Epstein-Barr infection 20
Exposures with potential association; more research is needed 20
Ultraviolet light exposure

Pesticides
Air pollution
Moderate alcohol consumption (more than 5 g, or half a drink, per day) is associated with a
reduced risk of systemic lupus erythematosus (hazard ratio, 0.61) 25
Diagnostic Procedures
Primary diagnostic tools

Establish the diagnosis based on characteristic
symptoms, signs, and immunologic abnormalities in
the absence of an alternative diagnosis 3 11
Diagnosis should be suspected in a female of

childbearing age presenting with a classic
constellation of clinical and laboratory findings. Butterfly malar erythema.
However, it may be overlooked initially in patients
presenting with single-organ involvement,
becoming evident only with development of

additional disease features
There is no definitive diagnostic laboratory test;

however, positive immunologic test results support
the diagnosis
Presence of (positive) antinuclear antibodies—in

conjunction with anti-dsDNA antibodies (against
Malar erythema (butterfly rash) and
double-stranded DNA), low complement levels, or
macular erythema on sun-exposed
anti-Sm antibodies—is highly suggestive of sites. - A young woman with malar
systemic lupus erythematosus in patients with erythema (butterfly rash) and
suspicious clinical findings 11 macular erythema on sun-exposed
sites of chest and extensor arms.
Initial testing strategy includes the following for Dorsal hand is also involved with
erythema in the interphalangeal
most patients; although practice patterns vary, areas and around nail folds. This
obtaining such testing before a rheumatologist patient was anti-Ro positive.
consultation is helpful
Antinuclear antibodies 11
If positive, reflex to broader autoantibody

panel which includes anti-ds DNA and
antibodies to extractable nuclear antigens
(anti-Sm and other relevant antibodies)
Papulosquamous lesions in patient
Complement levels (C3, C4, CH50) 11 with subacute cutaneous lupus
erythematosus. - Psoriasiform
Antiphospholipid antibodies (lupus lesions which coalesce to form
anticoagulant, anticardiolipin, anti–β₂- retiform arrays.
glycoprotein) 11
Direct Coombs test

Erythrocyte sedimentation rate or C-reactive
protein level Types of rashes seen in patients
with lupus. - Clinical manifestations
Testing to identify hematologic and renal of cutaneous lupus erythematosus.
A, Acute cutaneous erythematosus,
abnormalities showing "butterfly rash" on the face.
B, Subacute cutaneous lupus
Serum creatinine; typically ordered as part of erythematosus. The annular and
comprehensive metabolic panel polycyclic lesions were seen on the
chest and abdomen. Some lesions
CBC healed with hyperpigmentation. C,
Discoid lupus erythematosus.
Erosion and crusts were seen on
Urinalysis lower lip. D, Verrucous lupus
erythematosus lesion on hand,
showing well-demarcated elevated
Spot (random) urine protein to creatinine ratio plaque with verrucous sticky scales
to assess degree of proteinuria (if elevated, and fissures. E, Lupus
erythematosus profundus on the
result will be confirmed with 24-hour urine right cheek, showing indurated
collection for protein) reddish and yellowish plaque with
slight atrophy. F, Lupus
Additional first line testing, as indicated, based erythematosus tumidus with well-
on organ-specific symptoms/signs demarcated edematous reddish
plaque without scales. G, Chilblain
lupus erythematosus, showing
Chest radiograph to assess for pleural effusion erythematous and edematous
or other pulmonary disease if respiratory patches on the hands and fingers. H,
symptoms are present Neonatal lupus erythematosus,
showing multiple annular and
ECG and/or echocardiogram if pericarditis is polycyclic erythematous patches on
suspected the forehead, temple, and cheek.
Radiographs of affected joints
Additional targeted evaluation is typically at the

direction of an appropriate consultant;
depending on presentation, it may be urgent
Renal evaluation, including ultrasonography

and biopsy, if evidence of kidney involvement
26
Jaccoud arthropathy. - Note ulnar
deviation and joint subluxations. a,
Patients with glomerular hematuria and/or Clinical photograph. b, Radiograph
cellular casts, proteinuria greater than 0.5 of the same hands. Swan-neck
g/24 hours or spot urine protein to creatine deformities of fingers of both hands
are associated with generalized
ratio more than 500 mg/g, or unexplained osteoporosis, although it is more
decrease in glomerular filtration rate are striking in areas where cancellous
candidates for kidney biopsy 27 bone predominates. Erosions and
joint space narrowing are absent.
Patients with suspected lupus nephritis
should be tested for anti-dsDNA and anti-
C1q autoantibodies, antiphospholipid
antibodies, and complement levels (C3 and
C4) 27
Skin biopsy, if etiology of rash is uncertain
Neurologic evaluation (including MRI of brain,

lumbar puncture with cerebrospinal fluid
analysis, and/or cognitive testing, as
appropriate)
Pulmonary evaluation, including chest CT,

thoracentesis with evaluation of pleural fluid,
pulmonary function testing, and/or bronchosco

evaluation of abnormal chest radiograph findin
Cardiac evaluation, including transthoracic echo

pericardial involvement, valvular lesions, or pul
MRI for evaluation of myocarditis
Abdominal ultrasonography or CT, as directed b
Systemic lupus erythematosus classification criteria a

judgment; however, these criteria are not specifically
purpose of diagnosing systemic lupus erythematosus
Basing diagnosis on classification criteria alone m

undertreatment because patients may have disease
use clinical judgment and refer patients with unce
rheumatologist
With an established diagnosis, additional baseline diagn

for relevant comorbidities and for future monitoring
Lipid panel and fasting glucose level (or hemoglobin

abnormalities that contribute to atherosclerotic disea
patients with lupus 11
Vitamin D level to assess for deficiency (if deficiency

supplementation is advised) 3 11
Testing for chronic hepatitis B, hepatitis C, tuberculo

immunosuppressing drug therapies 11
Use results of history, physical examination, laboratory

determine current disease activity. Validated assessment
the use of these tools is recommended. Disease activity
performed by a rheumatologist
Some of the most commonly used include the follow
BILAG index (British Isles Lupus Assessment Grou

forms, including the BILAG 2004 28
SLEDAI (Systemic Lupus Erythematosus Disease A

are the SELENA-SLEDAI and SLEDAI-2K 29
Physician global assessment 30
Disease activity assessments commonly used in sy
BILAG index SLEDAI

Organ based (8 systems)
24 weighted varia
(clinical and labor
Evaluates preceding 8 months
related to 9 organ
systems
Ordinal scale for each organ system
ranging from A to E (A, highest disease
Evaluates previou
activity; E, no current or previous
days
organ involvement)
Caption: BILAG, British Isles Lupus Assessment Group; SLEDAI, System
Index.
Citation: Data from Durcan L et al: Management strategies and future directions
393(10188):2332-2343, 2019; Isenberg DA et al: BILAG 2004. Development and
Isles Lupus Assessment Group's disease activity index for patients with systemic
44(7):902-6, 2005; Bombardier C et al: Derivation of the SLEDAI. A disease activi
Prognosis Studies in SLE. Arthritis Rheum. 35(6):630-40, 1992; and Petri M et al
the routine clinic setting. J Rheumatol. 19(1):53-9, 1992.
Laboratory
Other diagnostic tools
Differential Diagnosis
Most common
Diagnosis may be challenging owing to diverse clinical manifestations and wide range of
differential diagnoses
Other autoimmune diseases with overlapping features; may be associated with

antinuclear antibodies
Rheumatoid arthritis (Related: Rheumatoid Arthritis)
Chronic autoimmune systemic inflammatory disease with articular and extra-

articular manifestations
Rheumatoid arthritis typically presents with insidious onset of symmetrical

polyarthritis over a period of weeks to months. Polyarthritis is usually symmetrical;
primarily affects small joints of extremities but may later involve large joints,
sparing thoracic and lumbar spine
Systemic manifestations may be similar to systemic lupus erythematosus, with

fatigue, weight loss, and fever. Extra-articular complications occur primarily in long-
standing, untreated disease and include pleuritis, pleural effusions, pneumonitis,
pericarditis, valvular heart disease, interstitial lung disease, and keratoconjunctivitis
sicca
Differentiate the 2 conditions based on radiographs of affected joints and serologic

test results
Patients with rheumatoid arthritis may have erosive joint changes on radiographs;
most patients with systemic lupus erythematosus do not (about 90%)
Positive rheumatoid factor and/or anti–cyclic citrullinated peptide antibody with
rheumatoid arthritis
Note: antinuclear antibodies may be present in patients with rheumatoid arthritis,

and rheumatoid factor (and less commonly, anti–cyclic citrullinated peptide
antibodies) may be present in some patients with systemic lupus erythematosus
2010 American College of Rheumatology/European League Against Rheumatism

classification criteria for rheumatoid arthritis requires the presence of synovitis in at
least 1 joint, absence of an alternative diagnosis that better explains synovitis, and a
qualifying score (at least 6 of a possible 10) 45
Sjögren syndrome
Common, chronic, multisystemic autoimmune disease that targets salivary and

lacrimal glands but can also involve other organ systems. May occur as an isolated
syndrome (primary Sjögren syndrome) or overlap with other connective tissue
diseases (secondary Sjögren syndrome)
Presents with dry, irritated eyes or dry mouth; parotid swelling may be present
Some patients develop systemic manifestations, including fatigue, Raynaud

phenomenon, cutaneous vasculitis and purpura, and polyarthralgia. A smaller
percentage may develop pulmonary or nervous system manifestations
Antinuclear antibodies result will be positive in most patients with primary Sjögren
syndrome (about 85%) 46
About half of patients have anti-Ro/SS-A and about a third have anti-La/SS-B

antibodies; overall, about a quarter to half of patients do not have either of these
antibody types 46
Diagnosis of primary Sjögren syndrome (and differentiation from systemic lupus

erythematosus) is usually made based on clinical features in conjunction with a
positive result for anti-Ro/SS-A and/or anti-La/SS-B antibodies. In patients without

these autoantibodies, biopsy of labial salivary glands can confirm the diagnosis
Dermatomyositis and polymyositis (Related: Polymyositis and Dermatomyositis)
Idiopathic inflammatory myopathy is characterized by proximal muscle weakness,

elevation of muscle enzyme levels, and the presence of inflammation on a muscle
biopsy
Muscle weakness is symmetric and develops over weeks to months; may have
characteristic skin findings (heliotrope rash; Gottron papules). Heliotrope rash can
also occur in systemic lupus erythematosus
Raynaud phenomenon, fever, polyarthritis, and interstitial lung disease may occur,
but nephritis and hematologic abnormalities are absent. A malar rash that can
mimic the butterfly rash of systemic lupus erythematosus may occur, but it does not
typically spare the nasolabial folds
Antinuclear antibodies result is often positive; myositis-associated antibodies (eg,
anti-Jo antibodies) suggest dermatomyositis/polymyositis
Differentiated based on clinical features (eg, absence of prominent symmetrical

muscle weakness in most patients with systemic lupus erythematosus, although
myositis can occur), muscle enzyme levels, presence of anti-Jo antibodies, and MRI
findings. Electrophysiologic testing, MRI, and muscle biopsy can confirm the
diagnosis if it cannot be made clinically
Systemic sclerosis (scleroderma)
Chronic, multisystem autoimmune disease that nearly always involves the skin and
is characterized by fibrosis and vascular dysfunction
Patients commonly present with distal finger swelling which progresses proximally
with development of cutaneous thickening, hardening, and fingertip ulcerations
Raynaud phenomenon is nearly always present. Fatigue is a prominent feature. May

develop pulmonary, gastrointestinal, renal, and cardiac complications
Antinuclear antibodies result is positive in most patients; a variety of systemic

sclerosis–related autoantibodies with high specificity for that disease may be
positive, including anti–Scl-70, anticentromere, and anti–RNA polymerase III
antibodies
Confirm the diagnosis and differentiate from systemic lupus erythematosus with
guidance from the classification criteria for systemic sclerosis by the American
College of Rheumatology and the European League Against Rheumatism 47
Drug-induced lupus erythematosus

Transient autoimmune syndrome associated with use of certain medications, in

particular hydralazine, procainamide, isoniazid, calcium channel blockers, terbinafine,
thiazide diuretics, minocycline, proton pump inhibitors, interferons, and tumor
necrosis factor α inhibitors
Manifestations resemble those of systemic lupus erythematosus, with arthralgia,

myalgia, fatigue, and serositis that begin typically several months after start of causative
drug (period ranges from weeks up to 2 years) and resolve after withdrawal of causative
drug 48
Renal involvement and neuropsychiatric involvement are rare. Major organ damage is
uncommon 48
Differentiated based on clinical features, medication history, and laboratory data,

including the pattern of autoantibodies that are present 49
Antinuclear antibodies result is positive in 90% to 100%, but anti-dsDNA and anti-
Sm antibodies are usually absent
Antihistone antibodies are present in 90% to 95% (but they may also be present in
60%-70% of patients with systemic lupus erythematosus)
Hypocomplementemia is uncommon (except for quinidine-induced forms)
Anemia, leukopenia, and thrombocytopenia are uncommon
Fibromyalgia
Chronic pain syndrome characterized by widespread musculoskeletal pain
Accompanied by significant fatigue and sleep disruption; headaches, irritable bowel

syndrome, and cognitive and mood disturbances are common
Skin rash and multiple organ involvement are absent
Antinuclear antibodies result is negative (however, in young female population,

prevalence of low-titer antinuclear antibodies is 20%) 32
Diagnosis is clinical and largely based on self-reported assessment 50
Disease activity scores are as follows:
Widespread pain index of 7 or more and symptom severity scale score of 5 or

more, or
Widespread pain index of 4 to 6 and symptom severity scale score of 9 or more
Generalized pain, defined as pain in at least 4 of 5 regions, must be present

(excluding jaw, chest, abdominal pain)
Symptoms have been present for 3 months or longer
Non-Hodgkin lymphoma
Heterogeneous group of lymphoproliferative disorders characterized by aberrant

proliferation of B cells, T cells, or natural killer cells
Often presents with lymphadenopathy. Constitutional symptoms, joint pain,

cytopenias (including autoimmune hemolytic anemia), lymphadenopathy, rash, and
positive antinuclear antibodies may be present and suggest the possibility of systemic
lupus erythematosus
Be particularly alert for non-Hodgkin lymphoma (and other malignancies) in older

patients presenting with new lupuslike syndromes
Differentiate based on histopathologic examination and immunohistochemical

analysis of excised lymph node
Treatment
Goals
Maintain lowest degree of disease activity possible, prevent flares, prevent organ damage,
minimize drug adverse effects, and improve quality of life
Durable complete remission is desirable but infrequent in systemic lupus erythematosus.

Attaining a lupus low disease activity state 52 is comparable with remission in preventing
flares and reducing the risk of future organ damage 51
Lupus low disease activity state is attained if the following conditions are met: 52
No new lupus disease activity compared with the previous assessment
A current prednisone (or equivalent) dose of 7.5 mg or less daily
Well-tolerated standard maintenance doses of immunosuppressive drugs and

approved biologic agents
A qualifying score on the following disease activity assessments:
SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) 29 (scale

0-105): a score of 4 or less, with no activity in major organ systems and no
hemolytic anemia or gastrointestinal activity
Physician Global Assessment 30 (scale 0-3): a score of 1 or 0
Disposition
Admission criteria
Hospitalization may be required to manage organ- or life-threatening manifestations such as
myocarditis, lupus nephritis, severe thrombocytopenia or hemolytic anemia, mesenteric
vasculitis, and central nervous system lupus 1
Criteria for ICU admission

Admit to ICU if life-threatening complications occur
Recommendations for specialist referral

All patients should have early consultation and regular follow-up with a rheumatologist
Multiorgan involvement is common and may require management by a multidisciplinary

team of subspecialists (eg, nephrologist, hematologist, neurologist; gastroenterologist,
dermatologist, obstetrician) 1
Patients with severe disease should be treated at a dedicated lupus center
Treatment Options
Hydroxychloroquine, an immunomodulator with antimalarial and antirheumatic indications,
is recommended for all patients with systemic lupus erythematosus, including those with
lupus nephritis, as soon as the diagnosis is made. Maintain treatment long term, regardless of
disease course and severity, unless toxicity occurs 2 26
Systematic review evaluated all published evidence of beneficial and adverse effects of
antimalarial therapy with hydroxychloroquine or chloroquine (randomized controlled trials
and observational studies; case reports were excluded except for toxicity reports) 53
High-quality evidence for reduction of activity of systemic lupus erythematosus and

reduction in mortality
High-quality evidence for decreased lupus activity in pregnant patients without fetal
adverse effect
Moderate-quality evidence for a protective effect on accrual of irreversible organ damage

and protection from thrombotic events
Toxicity was infrequent, mild, and usually reversible, with hydroxychloroquine having a
safer profile than chloroquine
Acute adverse effects were mainly cutaneous and gastrointestinal
In a large clinical cohort, risk of retinopathy was low in the first 5 years of treatment (1%),
but increased to 11.5% from 16 to 20 years of use. Older age, higher BMI, and higher blood
levels predicted retinopathy 54
Baseline retinal evaluation should be performed, with follow-up at 5 years and then
annually
Cardiac toxicity is rare
2 small studies (70 patients treated with hydroxychloroquine and 28 patients treated with
chloroquine) have evaluated cardiotoxicity (eg, QT prolongation and other conduction
abnormalities) of antimalarials in patients with systemic lupus erythematosus. No cases
of clinically relevant cardiotoxicity were reported 55 56
Case reports of cardiomyopathy associated with antimalarial drugs (primarily

chloroquine) are rare 57
Consider myocardial biopsy in a patient with systemic lupus erythematosus and

congestive heart failure
Chloroquine is used only if hydroxychloroquine is not available or not tolerated 11

Other pharmacologic therapies are added to control current disease activity and to manage
flares, with the goal of achieving either remission or lupus low disease activity state 2
Clinical practice guidelines base general treatment recommendations on severity of disease

activity; modify treatment based on specific clinical manifestations, comorbidities, and
therapeutic response
Disease activity categories in systemic lupus erythematosus.
Mild Moderate Severe

Clinically stable (no flares); no life- More severe manifestations, but not
Organ or life-threatening
threatening organ involvement organ- or life-threatening
Mild Moderate Severe

Examples:
Rash involving more than
Examples:
Examples: two-ninths of BSA
Major organ-threatening
Rash up to two-ninths of BSA
Constitutional symptoms disease:
Cutaneous vasculitis up to 18% of
Rash up to one-ninth of BSA - Nephritis
BSA
Arthralgia and/or mild arthritis - Cerebritis
Pleurisy
Mouth ulcers - Myelitis
Pericarditis
Platelet count of 50-100 × 10⁹ - Pneumonitis
Rheumatoid arthritis–like arthritis
cells/L - Mesenteric vasculitis
Platelet count of 20-50 × 10⁹ cells/L
Platelet count less than 20
× 10⁹ cells/L
Caption: BSA, body surface area.
Citation: From Fanouriakis A et al: 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann
Rheum Dis. 78(6):736-45, 2019.
Mild disease
Clinically stable disease with no life- or organ-threatening involvement and that is

unlikely to cause future organ damage
Treatment options include an antimalarial drug alone or in combination with short-term

glucocorticoids to induce disease control. Immunosuppressive drugs are sometimes
necessary
Remission may be achieved with an antimalarial drug alone
Glucocorticoids are necessary for some patients
Short-term oral or intramuscular glucocorticoids are often effective for mild joint
symptoms or flares 58
Improvement is similar with either approach, but response may be more rapid
with intramuscular steroids
For other manifestations (or if topical preparations are ineffective for cutaneous
disease), short courses of prednisone (up to 20 mg/day) are used but should be
tapered rapidly 11
Low-dose glucocorticoids may be required for maintenance; however, chronic use is
not considered an optimal strategy, so try to taper and discontinue 2 11
If necessary, a maintenance dose of 6 mg/day or less is preferable to higher doses, 3

59 because it is associated with the lowest additive risk of irreversible organ damage
compared with no steroid treatment 59
In patients not able to reduce systemic steroids to acceptable dosages for longer-term
use, addition of a cytotoxic-immunosuppressive drug (usually methotrexate or
azathioprine) can expedite the tapering/discontinuation of glucocorticoids 2
Type 2 (noninflammatory) symptoms, such as fatigue, diffuse pain, sleep disturbance,

and brain fog, will not respond to glucocorticoids; avoid "chasing" these symptoms
with increasing doses
NSAIDs or acetaminophen can be used for pain relief (eg, joint pain) and fever
management. Because of cardiovascular, gastrointestinal, and renal risks, use
judiciously and for short periods in patients at low risk of complications. Avoid
NSAIDs in patients with lupus nephritis 11
Because of rare case reports of an association of ibuprofen use with aseptic

meningitis in patients with systemic lupus erythematosus, some experts avoid
ibuprofen in favor of an alternative NSAID 60
Diclofenac gel can be considered instead of oral NSAIDs
Moderate disease
Increasingly severe manifestations, which if left untreated, may cause significant organ
damage. No immediate organ- or life-threatening disease is present
Treat with antimalarials plus bridging doses of glucocorticoids in combination with

cytotoxic-immunosuppressive agents (methotrexate and azathioprine; mycophenolate
mofetil for renal disease); consider belimumab if refractory 2 11
Reduce glucocorticoid to lowest possible maintenance dose as disease activity improves

and other immunosuppressive agents take effect
Safest dose for maintenance is 6 mg/day or less; 59 risk of irreversible organ damage
increases substantially at doses more than 7.5 mg/day
Administer a cytotoxic-immunosuppressive agent
Methotrexate has been evaluated in prospective case series and in 2 randomized

controlled trials 61 62 and found to be useful as a steroid-sparing agent, with
decreased disease activity, particularly in cutaneous and joint disease. Drug is
teratogenic and contraindicated in pregnancy 19
Azathioprine is nonteratogenic and is used primarily during pregnancy to control

renal and nonrenal disease activity; also effective as a steroid-sparing agent 63
Mycophenolate mofetil is a first line therapy in lupus nephritis and is also effective
in nonrenal disease. 64 65 Drug is teratogenic and contraindicated in pregnancy 3
In refractory cases of nonrenal lupus (residual disease activity not allowing tapering of
glucocorticoids despite immunosuppressive agents, and/or frequent relapses), consider
adding the biologic agent belimumab (a B-cell targeting agent) 2
Most beneficial for patients on glucocorticoid treatment at baseline with high

disease activity, low complement activity, and/or anti-dsDNA positivity 66
Meta-analysis and systematic review were performed to examine the role of biologic
disease-modifying drugs in patients with systemic lupus erythematosus
In adults with moderate to severe systemic lupus erythematosus despite

conventional immunosuppressive agents, adjunctive belimumab may offer
additional modest benefit (moderate-quality evidence from 2 randomized
controlled trials; 68 69 1125 patients) 67
Increases the rates of clinical response compared with immunosuppressive

agents alone, regardless of baseline severity and seropositivity
Prevents flares and allows reduction of prednisone dose
Does not increase the risk of serious intolerable adverse effects leading to
treatment discontinuation
Patients receiving belimumab had significantly less organ damage progression

compared with patients receiving standard of care in a propensity score-matched
comparative analysis of more than 500 patients 70
A Cochrane review of 6 randomized controlled trials found belimumab was effective
at reducing disease activity and need for glucocorticoids in patients with systemic
lupus erythematosus 71
Another meta-analysis showed the addition of belimumab to standard treatment

resulted in a renal response in patients with lupus nephritis 72
There is currently limited data demonstrating safety and long-term efficacy 73
Severe disease
More severe manifestations which are organ- or life-threatening; requires potent

immunosuppression
Severe life- or organ-threatening disease is treated with continuation of antimalarials and

a course of high-dose systemic glucocorticoids to induce disease control, either alone or
in combination with a cytotoxic-immunosuppressive agent (eg, mycophenolate mofetil or
cyclophosphamide). The biologic agent rituximab may be used in refractory cases 2
Drug- and organ-specific treatment considerations
Mycophenolate mofetil/mycophenolate acid or cyclophosphamide is first line agent, in

addition to 27glucocorticoids, for initial induction therapy in lupus nephritis; the
calcineurin inhibitor tacrolimus, and to a lesser extent, cyclosporine A also may have a
role either alone or in combination with mycophenolate mofetil/mycophenolate acid 74
27 26
After adequate response during the induction treatment, mycophenolate

mofetil/mycophenolate acid is continued as maintenance therapy;
cyclophosphamide induction is followed by either mycophenolate
mofetil/mycophenolate acid or azathioprine
Addition of belimumab to standard therapy improves renal response and may

reduce risk of relapse 27 75
Cyclophosphamide can also be considered for life- and organ-threatening

cardiopulmonary and neuropsychiatric disease. Gonadotoxic effects require caution in
both males and females of reproductive age
Rituximab is currently used only off-label for severe renal and extrarenal disease
refractory to other immunosuppressive agents and/or belimumab; it may be used
earlier in patients with contraindications to those drugs
Rituximab was not found to be more effective than standard of care in 2 randomized
controlled trials; 76 77 however, some disease features improved, including
thrombocytopenia and hypocomplementemia
In a prospective cohort study treating lupus nephritis with rituximab plus

mycophenolate mofetil but no oral steroids, partial or complete remission was
achieved by 90% 78
Hydroxychloroquine is recommended for all patients with lupus nephritis, in the

absence of contraindications 27
May consider using IV immunoglobulin and plasmapheresis to treat patients who have
refractory cytopenia or rapidly deteriorating acute confusional state 11
Treatment of cutaneous manifestations of lupus 2
Topical glucocorticoid preparations should be used first; topical tacrolimus may also be
helpful
Cutaneous manifestations that have not responded to topical agents may require systemic
corticosteroids as a bridging therapy
Addition of hydroxychloroquine, mepacrine, methotrexate, retinoids, dapsone, and

mycophenolate mofetil may be required for nonresponsive cases 79
Hydroxychloroquine, chloroquine, and methotrexate have the strongest evidence for

efficacy, based on limited randomized controlled trials in patients with systemic lupus
erythematosus and cutaneous disease 80 81
Guidelines for treatment of chronic cutaneous lupus are available from the British
Association of Dermatologists and the European Dermatology Forum in cooperation with
the European Academy of Dermatology and Venereology 79 82
Drug therapy
Antimalarial agents
Hydroxychloroquine
Preferred antimalarial agent 2
Hydroxychloroquine Sulfate Oral tablet; Children† and Adolescents†: 4 to 6 mg (3.1 to

4.6 mg base)/kg/day PO.
Hydroxychloroquine Sulfate Oral tablet; Adults: 200 mg (155 mg base) PO daily, 300 mg
(232 mg base) PO daily, or 400 mg (310 mg base) PO daily as a single dose or in 2
divided doses.
Specific preferred dosage has been controversial; many experts recommend 5 mg/kg or
less (using actual body weight) to decrease risk of retinopathy. 19 83 84
Chloroquine
Chloroquine Phosphate Oral tablet; Adults: 125 to 250 mg (75 to 150 mg base) PO once
daily. Max: 3.5 to 4 mg/kg/day.
Systemic corticosteroids
Low-dose oral corticosteroids, 6 mg/day or less, 59 are used to treat mild disease that does
not have major organ manifestations
Higher-dose oral or IV corticosteroids are used for major organ involvement and life-
threatening manifestations
Doses and route of administration depend on the type and severity of organ
involvement
Pulse doses of IV methylprednisolone, usually 250 to 1000 mg/day for 1 to 3

days, provide immediate therapeutic effect and enable the use of lower starting doses
of oral glucocorticoids 2
Early initiation of cytotoxic-immunosuppressive therapy can facilitate tapering and/or

discontinuation of steroids 2
When chronic maintenance treatment is required, decrease dose of prednisone to 6

mg/day or less 59 whenever possible to decrease accrual of irreversible organ damage
Immunosuppressive agents
Methotrexate 11
Teratogenic; cannot be used in pregnancy
Weekly doses of 15 mg or more are usually given via subcutaneous route
Methotrexate Sodium Oral tablet; Children and Adolescents: 5 to 10 mg/week PO

added to current SLE treatment; 8 of 10 patients able to reduce other SLE meds.
Methotrexate Sodium Oral tablet; Adults: 7.5 to 20 mg/week PO had led to reduced
disease activity and corticosteroid use in several studies.
Methotrexate Sodium Solution for injection; Adults: 5 to 10 mg IV/IM once weekly,

increase by 5 to 10 mg to Max: 50 mg/week. In 15 patients with cutaneous lupus
erythematosus, SC administration (7.5 to 20 mg/week) as effective as IV (7.5 to 20
mg/week) for 2 to 11 months.
Azathioprine 11
Azathioprine Oral tablet; Adults: Initially, 2 mg/kg/day PO. May titrate by 0.5 mg/kg as
indicated/tolerated. Max: 3.5 mg/kg/day PO for patients with normal thiopurine
methyltransferase (TPMT) activity. For patients with reduced TPMT activity
(heterozygotes), initiate with 0.75 mg/kg/day PO and titrate by 0.25 mg/kg; Max: 1.75
mg/kg/day PO. May be used with corticosteroids; used for maintenance therapy of SLE.
Mycophenolate mofetil 11
Consult a rheumatologist for appropriate dosage. Patients with Asian ancestry may
require lower doses
Teratogenic; cannot be used in pregnancy
Prescriber must document training in the Mycophenolate REMS (Risk Evaluation

and Mitigation Strategy) program for premenopausal females 85
Note that mycophenolate reduces the efficacy of oral contraceptives
Additional immunosuppressive agents for severe systemic lupus erythematosus; all are
prescribed and monitored by a rheumatologist
Cyclophosphamide
Tacrolimus 42
Biologic agents
Belimumab 86 87 88
Rituximab
Topical agents for cutaneous lupus 89
Topical corticosteroids
Fluocinonide (0.05%-0.1%)
Fluocinonide Topical gel; Children and Adolescents: Apply a thin layer topically to
the affected skin area(s) 2 to 4 times daily.
Fluocinonide Topical gel; Adults: Apply a thin layer topically to the affected skin
area(s) 2 to 4 times daily.
Multiple lesions should be treated sequentially, applying the medication to only a

small area of the skin at a time. Resistant dermatoses may require occlusion of the
affected areas.
Hydrocortisone (0.5%-1%)
Hydrocortisone Topical gel; Children and Adolescents 2 to 17 years: Apply sparingly

to affected areas 2 to 4 times per day. Follow the directions on the specific product
labeling. May use occlusive dressings for psoriasis or refractory conditions; however,
this can increase systemic absorption and the risk of adverse reactions. For self-
medication, apply a 0.5% or 1% non-prescription product to affected areas not more
than 3 to 4 times per day; discontinue if condition worsens or persists for more than
7 days.
Hydrocortisone Topical gel; Adults: Apply sparingly to affected areas 2 to 4 times per
day. Follow the directions on the specific product labeling. May use occlusive
dressings for psoriasis or refractory conditions; however, this can increase systemic
absorption and the risk of adverse reactions. For self-medication, apply a 0.5% or 1%
non-prescription product to affected areas not more than 3 to 4 times per day;
discontinue if condition worsens or persists for more than 7 days.
Nondrug and supportive care

Avoid triggers of lupus flares
Ultraviolet light
Avoiding UV light exposure is an important aspect of management because it can

exacerbate systemic and cutaneous manifestations
Avoid direct sunlight whenever possible; do not use tanning beds
Wear wide-brimmed hats and tightly woven clothing when outdoors
Use sunscreen that protects against both UV-A and UV-B light, with high sun
protection factor (ie, 50 or more) 19
Cigarette smoking
Counsel regarding the benefits of smoking cessation
Evidence-based strategies include nicotine replacement products, pharmacotherapy

(eg, bupropion, varenicline), and counseling 90 (Related: Tobacco Use Disorder and
Smoking Cessation)
Supplement with vitamin D if serum level is less than 40 nanograms/mL
Deficiency is common in patients with systemic lupus erythematosus and correlates with
increased disease activity
Vitamin D has an immunomodulatory effect, and supplementation is associated with

improvement in global disease activity scores, reduction in proteinuria, and higher
complement levels. 91 92
Aim for a target level of 40 nanograms/mL or more; recheck periodically 19
Optimize immunization status
Review vaccination status before initiation of immunosuppressive drugs
Clear benefits to vaccination with inactivated vaccines. In general, these should be given
according to recommended immunization schedules, with the following considerations:
19
Invasive pneumococcal disease is associated with significant morbidity and mortality

in patients with lupus. Administer pneumococcal vaccines (both 13-valent
pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine,
depending on earlier immunization history) to all patients according to CDC guidance
94 for patients with immunocompromising conditions 93
An annual inactivated influenza vaccine is recommended, though it may result in lower

seroprotection rates than in healthy controls 93
Reasonable to give the inactivated herpes zoster vaccine. It is safe and elicited an
appropriate antibody response in a study in patients with autoimmune disease,
although there is no disease-specific safety data for systemic lupus erythematosus 95
Reasonable to give human papillomavirus vaccine to patients aged 11 to 26 years; good

disease-specific safety data are available for the quadrivalent version of the vaccine 96
Avoid live vaccines if the patient is substantially immunosuppressed 19
Steroid dose causing substantial immunosuppression is considered to be 2 or more

weeks of daily receipt of 20 mg or 2 mg/kg of body weight of prednisone or equivalent
97
Also applies to patients being treated with methotrexate, azathioprine, mycophenolate,

cyclosporine, tacrolimus, and biologic drugs
Comorbidities
Antiphospholipid antibodies and antiphospholipid syndrome
Antiphospholipid antibodies (eg, lupus anticoagulant, anticardiolipin antibodies, anti–β₂-

glycoprotein 1 antibodies) are found in 30% to 40% of patients with systemic lupus
erythematosus when evaluated both serially and longitudinally 98
Antiphospholipid antibody syndrome manifests clinically as the occurrence of arterial or

venous thrombosis and/or obstetric morbidity in association with 1 or more of these
antibodies
Thrombotic morbidity
About half of patients with systemic lupus erythematosus and antiphospholipid

antibodies will have a venous or arterial thrombosis at some point. May occur as
deep vein thrombosis, pulmonary emboli, myocardial infarction, or stroke 99
Catastrophic thrombosis, with diffuse microvascular thrombosis of major organs, is

a rare occurrence, presenting with renal failure, acute respiratory distress syndrome,
encephalopathy, and/or other severe acute manifestations over a short period
The following factors are associated with higher thrombotic risk: 98 99
Triple positivity (all 3 antiphospholipid antibodies are present at 1 encounter) if

the anticardiolipin and anti–β₂-glycoprotein 1 are of the same isotype
Presence of lupus anticoagulant
High titers of anticardiolipin antibodies (especially IgG isotype)
Additional clinical factors that increase risk include hyperlipidemia,

hypertension, surgery, pregnancy, postpartum period, and exogenous estrogen
Obstetric morbidity
Obstetric antiphospholipid syndrome is defined as the occurrence of any of the

following in a patient with antiphospholipid antibodies:
3 or more early pregnancy losses (Related: Miscarriage and Recurrent Pregnancy

Loss)
1 or more late fetal losses
Severe preeclampsia in the setting of lupus anticoagulant (or moderate to high

titer anticardiolipin or anti–β₂-glycoprotein 1)
However, a large prospective multicenter study found that lupus anticoagulant (but
not other antiphospholipid antibodies) was associated with adverse pregnancy
outcomes 100
Management
Prevention and management of venous and arterial thrombosis
Identify and treat (or eliminate) modifiable thrombotic risk factors (eg,
hypertension, dyslipidemia, exogenous estrogen treatment). Statins may have an
antithrombotic effect
Primary thrombosis prophylaxis with low-dose aspirin has a protective effect in

patients with systemic lupus erythematosus and antiphospholipid antibodies; odds
ratio for thrombotic event was 0.55 in a meta-analysis 101
Because of potential bleeding risk with aspirin, it may be reasonable to treat only
those patients with high-risk antiphospholipid profile 2
If a thrombotic event occurs, start long-term secondary prophylaxis with warfarin
Based on 2 clinical trials, warfarin is the preferred long-term anticoagulant as

opposed to a direct oral anticoagulant 98
Both trials found an increased risk of arterial thrombosis in patients randomly

assigned to the trial's direct oral anticoagulant arm (rivaroxaban 102 in one trial;
apixaban 103 in the other), and both were terminated early
Both hydroxychloroquine and vitamin D supplementation (if levels are low) may
lower the risk of thrombosis 3 104
Prevention and management of obstetric morbidity
For patients with lupus anticoagulant or either of the other antiphospholipid

antibodies in medium to high titer, prophylaxis recommendations during
pregnancy vary based on patient history 98
For females with antiphospholipid antibodies but no prior pregnancy, or prior

pregnancy without miscarriage, or with 1 early miscarriage, treat with low-dose
aspirin 98
For females with multiple early miscarriages, a late fetal loss, or preeclampsia,
begin prophylactic heparin (usually given as low-molecular-weight heparin, twice
daily) as soon as pregnancy is confirmed 98 105
For females with a prior thrombotic event, begin full-dose heparin and low-dose
aspirin; use of aspirin is primarily to reduce the risk of preeclampsia 98
Accelerated atherosclerosis
Risk of cardiovascular events in patients with systemic lupus erythematosus is increased
2.66-fold 106
Rate of myocardial infarction is 50 times higher for a young female with systemic
lupus erythematosus than for a healthy female of similar age 107
Increased rates of subclinical atherosclerosis have also been demonstrated with

imaging studies
Elevated risk is associated with both disease-related and traditional factors
Disease-related factors that increase risk
High disease activity of systemic lupus erythematosus (average past levels) 106
Antiphospholipid antibodies
Corticosteroid use (current dose of 10 mg/day or more, or cumulative dose of more

than 10 mg/day for 10 years, increases cardiovascular events 106 in patients with
systemic lupus erythematosus)
Traditional risk factors (eg, smoking, hypertension, obesity, dyslipidemia, diabetes) also
contribute to risk. However, Framingham scores do not fully explain the high rates of
ischemic events 108
Risk management
Identify and treat any modifiable traditional cardiovascular risk factors
Smoking cessation (Related: Tobacco Use Disorder and Smoking Cessation)
Weight management if overweight or obese (Related: Obesity in Adults)
Avoid sedentary lifestyle

Manage hypertension (goal of 120/80 19), dyslipidemia, and diabetes according to

relevant clinical practice guidelines (Related: Hypertension)
Treat systemic lupus erythematosus with goal of attaining remission or lupus low
disease activity state, while minimizing cumulative corticosteroid dose
Aim for discontinuation of corticosteroids when possible, or maintenance dose of 6

mg/day or less (prednisone or equivalent), 59 which is associated with overall
decreased risk of irreversible organ damage
Decreased bone mineral density, osteopenia, and osteoporosis
Bone loss leading eventually to fractures is a common comorbidity in patients with

systemic lupus erythematosus 109
Bone loss occurs at younger age, and decreased bone mineral density has been
identified even in children with systemic lupus erythematosus
Osteopenia is present in 25% to 75% and osteoporosis in 10% to 68%, with the wide
ranges thought to be due to underscreening
5-fold increase in symptomatic fracture compared with risk in people without lupus
Risk factors include both traditional risk factors (eg, postmenopausal status, family
history, White or Asian ethnicity or race, smoking, excessive alcohol intake, low BMI) and
factors specific to lupus and its treatment (eg, low vitamin D level and corticosteroid
treatment)
Evaluating bone mineral density and osteoporotic risk
Obtain vitamin D level, and supplement to a level of 40 nanograms/mL or more;

recheck periodically
American College of Rheumatology guidelines recommend formal consideration of

fracture risk and risk management for all patients who begin corticosteroid treatment
Patients aged 40 years or older 110

Obtain bone mineral density testing
Use FRAX (Fracture Risk Assessment Tool) calculator to estimate percentage risk
and risk category (low, moderate, or high) for major osteoporotic fracture; this
guides decision on need for osteoporosis treatment
If prednisone dose is more than 7.5 mg/day, FRAX underestimates risk 110
Calculate adjusted FRAX risk with a correction factor: increase hip fracture
probability by 20% and overall fracture probability by 15%
Patients younger than 40 years 110
For patients with a new diagnosis of systemic lupus erythematosus who have
never had a bone density testing, obtain bone mineral density testing if there is a
history of a previous osteoporotic fracture
However, some experts obtain bone mineral density testing for all patients with
systemic lupus erythematosus regardless of age and other risk factors
Mitigation of bone loss
Correct reversible risk factors
Smoking cessation (Related: Tobacco Use Disorder and Smoking Cessation)
Limit alcohol intake to 1 or 2 alcoholic beverages per day 110
Maintain appropriate BMI (avoid being underweight)
Optimize calcium intake to 1000 to 1200 mg/day. Natural sources are preferred over
supplements which may increase coronary calcium deposition 110
Vitamin D supplementation to a level of 40 nanograms/mL or more; recheck
periodically 19
Minimize corticosteroid cumulative dose. Safest dose is 6 mg/day or less. 59 Use

steroid-sparing immunosuppressive therapies if necessary to achieve steroid tapering
and discontinuation
Treat patients at moderate or high fracture risk with an oral bisphosphonate.

Alternative therapies (IV bisphosphonates, teriparatide, denosumab) may be
appropriate alternatives in some cases 110
In patients with childbearing potential, bisphosphonates should be prescribed

only to those who are using effective birth control or are not sexually active
Fibromyalgia
Common comorbid condition in patients with systemic lupus erythematosus; prevalence

estimates range from 5% to 65% in multiple investigations 3
A patient satisfies the diagnosis of fibromyalgia by meeting criteria for widespread pain
and symptom severity in the context of consistent pain for at least 3 months, without
other explanation 50
Musculoskeletal pain due to fibromyalgia does not track with disease activity in lupus; it
is important to differentiate the cause of pain and not treat non–lupus-related pain with
lupus drugs
Patients with fibromyalgia tend to have increased fatigue both with psychosocial stresses
and with illness. This fatigue may be difficult to differentiate from fatigue associated with
lupus, but it will not respond to lupus treatment
Regular exercise and a stretching program can improve some symptoms, including
fatigue, pain, and cognitive dysfunction associated with fibromyalgia
Most patients with fibromyalgia treated with a combination of pharmacologic and

nonpharmacologic approaches report significant improvements in Revised Fibromyalgia
Impact Questionnaire scores
Special populations
Females of childbearing age
Contraception
A long-term reversible contraceptive is a good choice; hormonal intrauterine devices

can decrease blood loss, which can contribute to anemia
Depot medroxyprogesterone is also an option, but bone density must be monitored,

because osteopenia is an adverse effect
Combined oral contraceptives did not increase the risk of flare among females with
stable systemic lupus erythematosus in a randomized, placebo-controlled, multicenter
study 111
However, estrogen-containing contraceptives should be avoided in patients with

high disease activity and severe flares
Contraindicated if antiphospholipid antibodies are present
Preconception planning 112
Pregnancy is best planned for when systemic lupus erythematosus is well controlled
for at least 6 months on safe, nonteratogenic medications 113
If disease is not under good control, delay of pregnancy is recommended

Hydroxychloroquine is safe to use during pregnancy and should be continued
unless otherwise contraindicated
Pregnancy
Should be managed by an obstetrician at a high-risk center in consultation with a

rheumatologist
Pregnancy may increase disease activity and precipitate flares of lupus nephritis 113
Avoid prednisone if possible because it can increase pregnancy complications. If

mild, a nonrenal flare can be treated with intramuscular triamcinolone
Severe flares may require high-dose oral prednisone or IV methylprednisolone
Allowable (nonteratogenic) immunosuppressive drugs are azathioprine and

tacrolimus
Standard doses of hydroxychloroquine are first line systemic therapy for cutaneous
lupus during pregnancy. Dapsone is second line (give with folic acid 5 mg daily) 79
Stop NSAIDs before third trimester
High risk for maternal and fetal perinatal complications, including gestational
diabetes (especially with prednisone daily dose of more than 10 mg), preeclampsia
(especially with lupus nephritis), intrauterine growth restriction, intrauterine fetal
demise, premature rupture of membranes, preterm birth, and neonatal lupus 113
Patients with antiphospholipid antibodies require treatment with low-dose aspirin

and/or anticoagulation, depending on obstetric history 98
Neonatal lupus occurs in some babies born to mothers with anti-Ro/SS-A or anti-La/SS-B
antibodies; check for these antibodies before pregnancy, and if they are present, consider
fetal surveillance (echocardiography) for complete heart block from 16 to 28 weeks of
gestation 114
Children
Onset of systemic lupus erythematosus in a person younger than 18 years is termed

childhood-onset systemic lupus erythematosus 13
This type of lupus is associated with clinical manifestations similar to those of adult-
onset disease; however, clinical course is typically more severe
Renal and hematologic involvement, neurologic symptoms, and mucocutaneous

involvement are more common in childhood systemic lupus erythematosus 13
Pediatric rheumatologist should evaluate and manage care of children with clinical and
immunologic findings suggestive of systemic lupus erythematosus
Diagnosis and treatment are similar to those in adults 13
Monitoring
Monitor disease activity, comorbidities, and compliance with treatment recommendations
Patients with stable disease and lupus low disease activity state should be monitored every
6 months
Patients with active disease manifestations should be monitored more frequently, at 1- to

3-month intervals 11
Follow-up includes the following:
Focused history and physical examination, including assessment of cardiovascular risk

factors and calcium and vitamin D intake
Laboratory monitoring 11 115
Routine at all visits

CBC, serum creatinine, urinalysis, spot urine protein to creatinine ratio, and liver
function tests
Evaluation of serologic disease activity with anti-dsDNA and complement levels
Obtain additional laboratory testing as indicated by symptoms or signs
Periodically (annually, in most cases): lipid profile, fasting glucose level or hemoglobin
A1C, and vitamin D level
Assess disease activity using a validated disease activity index (eg, BILAG index, SLEDAI,
Physician Global Assessment, criteria for lupus low disease activity state, or other
appropriate index) 11
Assess for organ damage using the SLICC/ACR Damage Index 116 (annually, or more
frequently as indicated by disease activity) (SLICC/American College of Rheumatology)
Screening for hydroxychloroquine (or chloroquine) retinopathy 117 118
Ophthalmologic baseline examination should be performed within 1 year of starting

hydroxychloroquine or chloroquine in all patients
Begin annual screening within 5 years of treatment initiation
Primary screening tests are automated visual fields plus spectral domain optical
coherence tomography. 117 These should detect retinopathy before there is visual loss and
before it is visible on funduscopy
Complications and Prognosis
Complications
End-stage kidney disease (about 10% of patients with lupus nephritis progressed to this
within 10 years in an international cohort; other cohorts have reported higher percentages)
119
Atherosclerosis leading to myocardial infarction or other cardiovascular events
With high-risk antiphospholipid antibodies profile (ie, triple positivity, lupus anticoagulant,

high titers of anticardiolipin antibodies):
Venous and arterial thrombosis
Obstetric morbidity, including early pregnancy loss, late fetal demise, or preeclampsia
Treatment-related complications
Infection (due to both the underlying disease process and immunosuppressive

medication)
High-dose glucocorticoids, mycophenolate mofetil, and rituximab are associated with

increased infection risk
Osteoporosis and fragility fractures
Avascular necrosis of bone
Hypertension
Hyperglycemia/diabetes mellitus
Dyslipidemia
Hydroxychloroquine-related retinopathy after long-term use
Cardiomyopathy with resulting arrhythmias and heart failure after long-term use of
hydroxychloroquine or chloroquine 120
Prognosis
Systemic lupus erythematosus may be chronically active or have a relapsing (ie, flaring),
remitting disease course
Higher rate of flares is associated with younger age at disease onset, no use of antimalarials,
persistent generalized disease activity, and persistent serologic activity (eg, anti-dsDNA, low
complement levels) 2
Duration of time within lupus low disease activity state has a dose-dependent relationship
to reduced organ damage accrual. Being in this state is also associated with fewer flares.
These improved outcomes are independent of baseline damage, or of higher baseline
disease activity 121
Systemic lupus erythematosus is associated with increased mortality
Increased all-cause mortality compared with general population without lupus, with a
standardized mortality ratio (ie, ratio of deaths observed to deaths expected) of 2.4
122 to 5.3 123 19
Early deaths are most frequently attributable to active disease and infections 19
Later deaths are generally attributable to cumulative organ damage, atherosclerotic

cardiovascular disease, or treatment-related complications 19
10-year survival of 91%; 20-year survival of 78% 124
References
1 Chowdhary VR: Broad concepts in management of systemic lupus erythematosus. Mayo Clin Proc.
92(5):744-61, 2017
View In Article | Cross Reference (https://pubmed.ncbi.nlm.nih.gov/28473038)
2 Fanouriakis A et al: 2019 update of the EULAR recommendations for the management of systemic
lupus erythematosus. Ann Rheum Dis. 78(6):736-45, 2019
3 Fava A et al: Systemic lupus erythematosus: diagnosis and clinical management. J Autoimmun. 96:1-
13, 2019
4 Aggarwal R et al: Distinctions between diagnostic and classification criteria? Arthritis Care Res
(Hoboken). 67(7):891-7, 2015
5 Aringer M et al: 2019 European League Against Rheumatism/American College of Rheumatology

classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 78(9):1151-9, 2019
6 Petri M et al: Derivation and validation of the Systemic Lupus International Collaborating Clinics
classification criteria for systemic lupus erythematosus. Arthritis Rheum. 64(8):2677-86, 2012
7 Yazdany J et al: Definition and classification of lupus and lupus-related disorders. In: Wallace DJ et al,
eds: Dubois' Lupus Erythematosus and Related Syndromes. 9th ed. Elsevier; 2019:15-22
View In Article | Cross Reference (https://www.clinicalkey.com/#!/content/book/3-s2.0-
B9780323479271000025?scrollTo=%23top)
8 Dall'Era M et al: Clinical features of systemic lupus erythematosus. In: Firestein GS et al, eds: Kelley
and Firestein's Textbook of Rheumatology. 10th ed. Elsevier; 2017:1345-67.e3
View In Article | Cross Reference (https://www.clinicalkey.com//#!/content/book/3-s2.0-
B9780323316965000802)
9 Pisetsky DS et al: A novel system to categorize the symptoms of systemic lupus erythematosus.
Arthritis Care Res (Hoboken). 71(6):735-41, 2019
10 Crow MK: Systemic lupus erythematosus. In: Goldman L et al, eds: Goldman-Cecil Medicine. 26th ed.
Elsevier; 2020:1725-34.e2
B9780323532662002502)
11 Gordon C et al: The British Society for Rheumatology guideline for the management of systemic
lupus erythematosus in adults: executive summary. Rheumatology (Oxford). 57(1):14-8, 2018
12 Petri M et al: Cognitive function in a systemic lupus erythematosus inception cohort. J Rheumatol.
35(9):1776-81, 2008
13 Harry O et al: Childhood-onset systemic lupus erythematosus: a review and update. J Pediatr. 196:22-
30.e2, 2018
14 Cervera R et al: Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a
comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore).
82(5):299-308, 2003
15 Crow MK: Etiology and pathogenesis of systemic lupus erythematosus. In: Firestein GS et al, eds:
Kelley and Firestein's Textbook of Rheumatology. 10th ed. Elsevier; 2017:1329-44
B9780323316965000796)
16 Mina R et al: Update on differences between childhood-onset and adult-onset systemic lupus
erythematosus. Arthritis Res Ther. 15(4):218, 2013
17 Generali E et al: Lessons learned from twins in autoimmune and chronic inflammatory diseases. J
Autoimmun. 83:51-61, 2017
18 Murashima A et al: Long term prognosis of children born to lupus patients. Ann Rheum Dis. 63(1):50-
3, 2004
19 Durcan L et al: Management strategies and future directions for systemic lupus erythematosus in
adults. Lancet. 393(10188):2332-43, 2019
20 Parks CG et al: Understanding the role of environmental factors in the development of systemic lupus
erythematosus. Best Pract Res Clin Rheumatol. 31(3):306-20, 2017
21 Finckh A et al: Occupational silica and solvent exposures and risk of systemic lupus erythematosus in
urban women. Arthritis Rheum. 54(11):3648-54, 2006
22 Costenbader KH et al: Cigarette smoking and the risk of systemic lupus erythematosus: a meta-
analysis. Arthritis Rheum. 50(3):849-57, 2004
23 Chua MHY et al: Association between cigarette smoking and systemic lupus erythematosus--an
updated multivariate Bayesian metaanalysis. J Rheumatol. ePub, 2019
24 Costenbader KH et al: Reproductive and menopausal factors and risk of systemic lupus
erythematosus in women. Arthritis Rheum. 56(4):1251-62, 2007
25 Barbhaiya M et al: Influence of alcohol consumption on the risk of systemic lupus erythematosus
among women in the nurses' health study cohorts. Arthritis Care Res (Hoboken). 69(3):384-92, 2017
26 KDIGO Glomerular Diseases Work Group: KDIGO 2021 Clinical Practice Guideline for the
Management of Glomerular Diseases. Kidney Disease: Improving Global Outcomes. KDIGO website.
Accessed March 27, 2022. https://kdigo.org/wp-content/uploads/2017/02/KDIGO-Glomerular-

Diseases-Guideline-2021-English.pdf
View In Article | Cross Reference (https://kdigo.org/wp-content/uploads/2017/02/KDIGO-Glomerular-
Diseases-Guideline-2021-English.pdf )
27 Fanouriakis A et al: 2019 update of the Joint European League Against Rheumatism and European
Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA)
recommendations for the management of lupus nephritis. Ann Rheum Dis. 79(6):713-23, 2020
28 Isenberg DA et al: BILAG 2004. Development and initial validation of an updated version of the
British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus
erythematosus. Rheumatology (Oxford). 44(7):902-6, 2005
29 Gladman DD et al: Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 29(2):288-
91, 2002
30 Petri M et al: Validity and reliability of lupus activity measures in the routine clinic setting. J
Rheumatol. 19(1):53-9, 1992
31 Apostolopoulos D et al: Systemic lupus erythematosus--when to consider and management options.

Aust Fam Physician. 42(10):696-700, 2013
32 Gatto M et al: Preclinical and early systemic lupus erythematosus. Best Pract Res Clin Rheumatol.
33(4):101422, 2019
33 Benito-Garcia E et al: Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-
Sm and anti-RNP antibody tests. Arthritis Rheum. 51(6):1030-44, 2004
34 Gheita TA et al: Anti-dsDNA titre in female systemic lupus erythematosus patients: relation to disease
manifestations, damage and antiphospholipid antibodies. Lupus. 27(7):1081-7, 2018
35 Conti F et al: Systemic lupus erythematosus with and without anti-dsDNA antibodies: analysis from a
large monocentric cohort. Mediators Inflamm. 2015:328078, 2015
36 Peng SL et al: Anti-nuclear antibodies. In: Firestein GS et al, eds: Kelley and Firestein's Textbook of
Rheumatology. 10th ed. Elsevier; 2017:817-30
B9780323316965000553?scrollTo=%23hl0001253)
37 Petri M: Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun. 15(2):145-51, 2000

38 Pengo V et al: Incidence of a first thromboembolic event in asymptomatic carriers of high-risk

antiphospholipid antibody profile: a multicenter prospective study. Blood. 118(17):4714-8, 2011
39 Gladman DD et al: Serologically active clinically quiescent systemic lupus erythematosus: a

discordance between clinical and serologic features. Am J Med. 66(2):210-5, 1979
40 Cascio MJ et al: Anemia: evaluation and diagnostic tests. Med Clin North Am. 101(2):263-84, 2017
41 Matar HE et al: Correlation of 24-hour urinary protein quantification with spot urine
protein:creatinine ratio in lupus nephritis. Lupus. 21(8):836-9, 2012
42 Hahn BH et al: American College of Rheumatology guidelines for screening, treatment, and
management of lupus nephritis. Arthritis Care Res (Hoboken). 64(6):797-808, 2012
43 Parikh SV et al: Update on lupus nephritis: Core Curriculum 2020. Am J Kidney Dis. 76(2):265-81,
2020
44 O'Neill S et al: Systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 24(6):841-55, 2010
45 Neogi T et al: The 2010 American College of Rheumatology/European League Against Rheumatism
classification criteria for rheumatoid arthritis: phase 2 methodological report. Arthritis Rheum.
62(9):2582-91, 2010
46 St Clair EW et al: Sjögren's syndrome. In: Firestein GS et al, eds: Kelley and Firestein's Textbook of
Rheumatology. 10th ed. Elsevier; 2017:1221-44.e4
B9780323316965000735?scrollTo=%23hl0000949)
47 van den Hoogen F et al: 2013 classification criteria for systemic sclerosis: an American College of
Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum.
65(11):2737-47, 2013
48 Antonov D et al: Drug-induced lupus erythematosus. Clin Dermatol. 22(2):157-66, 2004

49 Vaglio A et al: Drug-induced lupus: traditional and new concepts. Autoimmun Rev. 17(9):912-8, 2018
50 Wolfe F et al: 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum.
46(3):319-29, 2016
51 Petri M et al: Comparison of remission and lupus low disease activity state in damage prevention in a
United States systemic lupus erythematosus cohort. Arthritis Rheumatol. 70(11):1790-5, 2018
52 Franklyn K et al: Definition and initial validation of a lupus low disease activity state (LLDAS). Ann
Rheum Dis. 75(9):1615-21, 2016
53 Ruiz-Irastorza G et al: Clinical efficacy and side effects of antimalarials in systemic lupus
erythematosus: a systematic review. Ann Rheum Dis. 69(1):20-8, 2010
54 Petri M et al: Hydroxychloroquine blood levels predict hydroxychloroquine retinopathy. Arthritis

Rheumatol. 72(3):448-53, 2020
55 Costedoat-Chalumeau N et al: Heart conduction disorders related to antimalarials toxicity: an

analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue
diseases. Rheumatology (Oxford). 46(5):808-10, 2007
56 Wozniacka A et al: The cardiac safety of chloroquine phosphate treatment in patients with systemic
lupus erythematosus: the influence on arrhythmia, heart rate variability and repolarization
parameters. Lupus. 15(8):521-5, 2006
57 Avina-Zubieta JA et al: Antimalarial medications. In: Wallace DJ et al, eds: Dubois' Lupus
Erythematosus and Related Syndromes. 9th ed. Elsevier; 2019:650-60
B9780323479271000529?scrollTo=%23hl0000782)
58 Danowski A et al: Flares in lupus: Outcome Assessment Trial (FLOAT), a comparison between oral
methylprednisolone and intramuscular triamcinolone. J Rheumatol. 33(1):57-60, 2006
59 Thamer M et al: Prednisone, lupus activity, and permanent organ damage. J Rheumatol. 36(3):560-4,
2009
60 Lee CH et al: Principles of therapy, local measures, and NSAIDs. In: Wallace DJ et al, eds: Dubois'
Lupus Erythematosus and Related Syndromes. 9th ed. Elsevier; 2019:640-9
B9780323479271000517?scrollTo=%23hl0000739)
61 Fortin PR et al: Steroid-sparing effects of methotrexate in systemic lupus erythematosus: a double-

blind, randomized, placebo-controlled trial. Arthritis Rheum. 59(12):1796-804, 2008
62 Carneiro JR et al: Double blind, randomized, placebo controlled clinical trial of methotrexate in
systemic lupus erythematosus. J Rheumatol. 26(6):1275-9, 1999
63 Griffiths B et al: The BILAG multi-centre open randomized controlled trial comparing ciclosporin vs
azathioprine in patients with severe SLE. Rheumatology (Oxford). 49(4):723-32, 2010
64 Ginzler EM et al: Nonrenal disease activity following mycophenolate mofetil or intravenous

cyclophosphamide as induction treatment for lupus nephritis: findings in a multicenter, prospective,
randomized, open-label, parallel-group clinical trial. Arthritis Rheum. 62(1):211-21, 2010
65 Mok CC: Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a
systematic review. Scand J Rheumatol. 36(5):329-37, 2007
66 van Vollenhoven RF et al: Belimumab in the treatment of systemic lupus erythematosus: high disease
activity predictors of response. Ann Rheum Dis. 71(8):1343-9, 2012
67 Shamliyan TA et al: Additional improvements in clinical response from adjuvant biologic response
modifiers in adults with moderate to severe systemic lupus erythematosus despite
immunosuppressive agents: a systematic review and meta-analysis. Clin Ther. ePub, 2017
68 Furie R et al: A phase III, randomized, placebo-controlled study of belimumab, a monoclonal

antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.
Arthritis Rheum. 63(12):3918-30, 2011
69 Navarra SV et al: Efficacy and safety of belimumab in patients with active systemic lupus
erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 377(9767):721-31, 2011
70 Urowitz MB et al: Organ damage in patients treated with belimumab versus standard of care: a
propensity score-matched comparative analysis. Ann Rheum Dis. 78(3):372-9, 2019
71 Singh JA et al: Belimumab for systemic lupus erythematosus. Cochrane Database Syst Rev.
2:CD010668, 2021
72 Shrestha S et al: Belimumab in lupus nephritis: a systematic review and meta-analysis. Cureus.
13(12):e20440, 2021
73 Iolascon G: What are the benefits and harms of belimumab for patients with systemic lupus
erythematosus?: a Cochrane review summary with commentary. Int J Rheum Dis. 24(10):1331-3, 2021
74 Hannah J et al: Tacrolimus use in lupus nephritis: a systematic review and meta-analysis. Autoimmun
Rev. 15(1):93-101, 2016
75 Furie R et al: Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med.
383(12):1117-28, 2020
76 Merrill JT et al: Efficacy and safety of rituximab in moderately-to-severely active systemic lupus
erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation
of rituximab trial. Arthritis Rheum. 62(1):222-33, 2010
77 Rovin BH et al: Efficacy and safety of rituximab in patients with active proliferative lupus nephritis:
the lupus nephritis assessment with rituximab study. Arthritis Rheum. 64(4):1215-26, 2012
78 Condon MB et al: Prospective observational single-centre cohort study to evaluate the effectiveness of
treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum
Dis. 72(8):1280-6, 2013
79 O'Kane D et al: British Association of Dermatologists guidelines for the management of people with
cutaneous lupus erythematosus 2021. Br J Dermatol. 185(6):1112-23, 2021
80 Hannon CW et al: Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane
Database Syst Rev. 3:CD007478, 2021
81 Sprow G et al: Interventions for cutaneous disease in systemic lupus erythematosus: summary of a
Cochrane review. JAMA Dermatol. ePub, 2022
82 Kuhn A et al: S2k guideline for treatment of cutaneous lupus erythematosus--guided by the European
Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and
Venereology (EADV). J Eur Acad Dermatol Venereol. 31(3):389-404, 2017
83 Durcan L et al: Hydroxychloroquine blood levels in systemic lupus erythematosus: clarifying dosing
controversies and improving adherence. J Rheumatol. 42(11):2092-7, 2015
84 Melles RB et al: The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.
JAMA Ophthalmol. 132(12):1453-60, 2014
85 Mycophenolate REMS program: Mycophenolate REMS website. Accessed March 27, 2022.
https://www.mycophenolaterems.com/#Main
View In Article | Cross Reference (https://www.mycophenolaterems.com/#Main)
86 Wise LM et al: The safety of belimumab for the treatment of systemic lupus erythematosus. Expert
Opin Drug Saf. 18(12):1133-44, 2019
87 Manzi S et al: Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity

across multiple organ domains in patients with systemic lupus erythematosus: combined results
from two phase III trials. Ann Rheum Dis. 71(11):1833-8, 2012
88 Strand V et al: Improvements in health-related quality of life with belimumab, a B-lymphocyte

stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus
from the randomised controlled BLISS trials. Ann Rheum Dis. 73(5):838-44, 2014
89 Jessop S et al: Drugs for discoid lupus erythematosus. Cochrane Database Syst Rev. 5:CD002954, 2017
90 Stead LF et al: Combined pharmacotherapy and behavioural interventions for smoking cessation.
Cochrane Database Syst Rev. 2016(3):CD008286, 2016
91 Petri M et al: Vitamin D in systemic lupus erythematosus: modest association with disease activity
and the urine protein-to-creatinine ratio. Arthritis Rheum. 65(7):1865-71, 2013
92 Lima GL et al: Vitamin D supplementation in adolescents and young adults with juvenile systemic
lupus erythematosus for improvement in disease activity and fatigue scores: a randomized, double-
blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 68(1):91-8, 2016
93 Garg M et al: Recommendations and barriers to vaccination in systemic lupus erythematosus.

Autoimmun Rev. 17(10):990-1001, 2018
94 CDC: Pneumococcal Vaccination: Summary of Who and When to Vaccinate. CDC website. Reviewed
January 24, 2022. Accessed March 27, 2022. https://www.cdc.gov/vaccines/vpd/pneumo/hcp/who-when-
to-vaccinate.html
View In Article | Cross Reference (https://www.cdc.gov/vaccines/vpd/pneumo/hcp/who-when-to-
vaccinate.html)
95 Eberhardson M et al: Safety and immunogenicity of inactivated varicella-zoster virus vaccine in adults
with autoimmune disease: a phase 2, randomized, double-blind, placebo-controlled clinical trial. Clin
Infect Dis. 65(7):1174-82, 2017
96 Mok CC: Investigations and management of gastrointestinal and hepatic manifestations of systemic
lupus erythematosus. Best Pract Res Clin Rheumatol. 19(5):741-66, 2005
97 CDC: Contraindications and Precautions: General Best Practice Guidelines for Immunization: Best
Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). CDC website.
Reviewed March 15, 2022. Accessed February 10, 2022. https://www.cdc.gov/vaccines/hcp/acip-
recs/general-recs/contraindications.html
View In Article | Cross Reference (https://www.cdc.gov/vaccines/hcp/acip-recs/general-
recs/contraindications.html)
98 Petri M: Antiphospholipid syndrome. Transl Res. ePub, 2020

99 Domingues V et al: Assessment of the independent associations of IgG, IgM and IgA isotypes of
anticardiolipin with thrombosis in SLE. Lupus Sci Med. 3(1):e000107, 2016
100 Yelnik CM et al: Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-
positive patients: validation of PROMISSE study results. Lupus Sci Med. 3(1):e000131, 2016
101 Arnaud L et al: Efficacy of aspirin for the primary prevention of thrombosis in patients with
antiphospholipid antibodies: an international and collaborative meta-analysis. Autoimmun Rev.
13(3):281-91, 2014
102 Pengo V et al: Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood.
132(13):1365-71, 2018
103 Woller SC et al: Apixaban for the Secondary Prevention of Thrombosis Among Patients With
Antiphospholipid Syndrome: study rationale and design (ASTRO-APS). Clin Appl Thromb Hemost.
22(3):239-47, 2016
104 Bonventre JV: Antifibrotic vitamin D analogs. J Clin Invest. 123(11):4570-3, 2013
105 Liu X et al: Comparison of therapeutic interventions for recurrent pregnancy loss in association with
antiphospholipid syndrome: a systematic review and network meta-analysis. Am J Reprod Immunol.
83(4):e13219, 2020
106 Magder LS et al: Incidence of and risk factors for adverse cardiovascular events among patients with
systemic lupus erythematosus. Am J Epidemiol. 176(8):708-19, 2012
107 Giannelou M et al: Cardiovascular disease in systemic lupus erythematosus: a comprehensive update.
J Autoimmun. 82:1-12, 2017
108 Esdaile JM et al: Traditional Framingham risk factors fail to fully account for accelerated
atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 44(10):2331-7, 2001
109 Edens C et al: Systemic lupus erythematosus, bone health, and osteoporosis. Curr Opin Endocrinol
Diabetes Obes. 22(6):422-31, 2015
110 Buckley L et al: 2017 American College of Rheumatology guideline for the prevention and treatment
of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. 69(8):1521-37, 2017
111 Petri M et al: Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J
Med. 353(24):2550-8, 2005
112 Bertsias G et al: Treatment of systemic lupus erythematosus. In: Firestein GS et al, eds: Kelley and
Firestein's Textbook of Rheumatology. 10th ed. Elsevier; 2017:1368-88.e5
B9780323316965000814)
113 Petri M: Pregnancy and systemic lupus erythematosus. Best Pract Res Clin Obstet Gynaecol. 64:24-30,
2020
114 Clowse MEB et al: The prevention, screening and treatment of congenital heart block from neonatal
lupus: a survey of provider practices. Rheumatology (Oxford). 57(suppl 5):v9-17, 2018
115 Tunnicliffe DJ et al: Diagnosis, monitoring, and treatment of systemic lupus erythematosus: a
systematic review of clinical practice guidelines. Arthritis Care Res (Hoboken). 67(10):1440-52, 2015
116 Gladman DD et al: The Systemic Lupus International Collaborating Clinics/American College of
Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International
comparison. J Rheumatol. 27(2):373-6, 2000
117 Rosenbaum JT et al: American College of Rheumatology, American Academy of Dermatology,

Rheumatologic Dermatology Society, and American Academy of Ophthalmology 2020 joint statement
on hydroxychloroquine use with respect to retinal toxicity. Arthritis Rheumatol. 73(6):908-11, 2021
118 Marmor MF et al: Recommendations on screening for chloroquine and hydroxychloroquine

retinopathy (2016 revision). Ophthalmology. 123(6):1386-94, 2016
119 Hanly JG et al: The frequency and outcome of lupus nephritis: results from an international
inception cohort study. Rheumatology (Oxford). 55(2):252-62, 2016
120 Desmarais J et al: American College of Rheumatology white paper on antimalarial cardiac toxicity.
Arthritis Rheumatol. 73(12):2151-60, 2021
121 Golder V et al: Lupus low disease activity state as a treatment endpoint for systemic lupus
erythematosus: a prospective validation study. Lancet Rheumatol. 1(2):e95-102, 2019
View In Article | Cross Reference (https://doi.org/10.1016/S2665-9913(19)30037-2)
122 Bernatsky S et al: Mortality in systemic lupus erythematosus. Arthritis Rheum. 54(8):2550-7, 2006
123 Mok CC et al: Life expectancy, standardized mortality ratios, and causes of death in six rheumatic
diseases in Hong Kong, China. Arthritis Rheum. 63(5):1182-9, 2011
124 Kasitanon N et al: Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore).
85(3):147-56, 2006
(https://play.google.com/store/apps/details?id=com.elsevier.cs.ck&hl=en)
(https://itunes.apple.com/us/app/clinicalkey/id1041998175) (https://www.facebook.com/ClinicalKey)
(https://www.linkedin.com/company/3969981) (https://www.twitter.com/ClinicalKey)
(http://www.elsevier.com/)
Contact Us (https://service.elsevier.com/app/contact/supporthub/clinicalkey/)
Resource Center (https://elsevierresources.com/clinicalkey/resource-centers/)
Terms & Conditions (https://www.elsevier.com/legal/elsevier-website-terms-and-conditions)
Privacy Policy (https://www.elsevier.com/legal/privacy-policy)
Registered User Agreement (http://www.elsevier.com/legal/elsevier-registered-user-agreement)
Help (https://service.elsevier.com/app/home/supporthub/clinicalkey/)
Accessibility (https://service.elsevier.com/app/answers/detail/a_id/19138/c/10546/supporthub/clinicalkey/)
(https://www.elsevier.com/legal/elsevier-website-terms-and-conditions)
(http://www.elsevier.com/legal/privacy-policy)
We use cookies to help provide and enhance our service and tailor content. By continuing you agree to the use of
cookies (http://www.elsevier.com/legal/use-of-cookies).
Copyright © 2023 Elsevier B.V. or its licensors or contributors.
(http://www.relx.com/)

English - Systemic Lupus Erythematosus - ClinicalKey

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

English - Systemic Lupus Erythematosus - ClinicalKey

Uploaded by

Copyright:

Available Formats

3/27/23, 12:14 AM Systemic Lupus Erythematosus - ClinicalKey

Diagnosis should be suspected in a female of childbearing age presenting with a classic

diagnosing systemic lupus erythematosus

Hydroxychloroquine, an antimalarial and antirheumatic immunomodulator, is the

Additional pharmacotherapy is individualized according to clinical manifestations, specific

Glucocorticoids are prescribed for disease flares, with a goal of discontinuation. If

Cytotoxic-immunosuppressive agents (eg, methotrexate, azathioprine, mycophenolate,

Comorbidities associated with systemic lupus erythematosus include antiphospholipid

Nonpharmacologic measures (eg, sun protection), reducing cardiovascular risk, and

Before attributing fever to systemic lupus erythematosus disease activity, consider

Designed primarily to create homogeneous cohorts for clinical research; 4 however,

Most recent classification criteria are as follows:

2019 European League Against Rheumatism/American College of Rheumatology

Weighted multicriteria system, with a positive antinuclear antibodies titer (1:80 or

Points are accumulated from clinical findings (ie, constitutional, hematologic,

Patients accumulating 10 or more points are classified

SLICC (Systemic Lupus International Collaborating Clinics) criteria of 2012 6

the presence of antinuclear antibodies or anti-dsDNA (double-stranded DNA)

Categorization of lupus and lupus-related disorders based on phenotype

Systemic lupus erythematosus

Multisystemic involvement of skin, joints, serosal membranes, hematologic system,

Chronic cutaneous lupus erythematosus

Drug-induced lupus erythematosus

Passive transfer of certain autoantibodies (anti-Ro/SS-A, anti-La/SS-B) which may be

Time lag to recognition of symptoms as systemic lupus erythematosus (months to years)

Unexplained fever (after other causes, such as infections, are excluded)

Anorexia and mild weight loss

Symptoms associated with systemic lupus erythematosus but not related to

Marked fatigue, often described as disabling

Widespread or diffuse pain

Anxiety and/or depression

Occurs on sun-exposed areas, with onset a day or two after exposure

Hair thinning and breakage

Morning stiffness of at least 30 minutes in the proximal interphalangeal, metacarpal-

Joint pain or swelling in the hands

Pleuritis, manifested as pleuritic chest pain lasting more than 1 day 11

Central nervous system

Difficulties with memory (may be a noninflammatory, type II symptom)

Acute confusional state

Stroke (often mediated by antiphospholipid antibodies or hypertension)

Spinal cord dysfunction due to myelitis (rare)

Peripheral nervous system

Peripheral neuropathies, including small fiber neuropathy and mononeuritis

Anemia (often multifactorial) is present in 57%; may contribute to fatigue 10

Mild (asymptomatic) thrombocytopenia is present in about 50%, but if severe, may

Leukopenia (most commonly lymphopenia; neutropenia may also be present) in up to

Raynaud phenomenon (44%) 10

Venous or arterial thromboembolism (suggests the possibility of antiphospholipid

Other organ involvement can result in a wide variety of symptomatic presentations

Dry, irritated eyes (keratoconjunctivitis sicca)

Interstitial lung disease

Accelerated atherosclerosis with coronary artery disease

Valvular dysfunction (often due to antiphospholipid antibodies)

Mesenteric and intestinal vasculitis

Obstetric, often due to antiphospholipid antibody syndrome

Late fetal loss

Cervical, axillary, and inguinal nodes most commonly involved

Lymph nodes are soft and nontender

Splenomegaly may be present

Cutaneous manifestations specific to lupus

Acute forms (transient, nonscarring) are located on sun-exposed skin

Erythema (mild to intense) on malar areas bilaterally, sparing nasolabial folds

May also cover bridge of nose

Telangiectasias, papules, scale and crust, dyspigmentation, and epidermal atrophy