In theClinic

In the Clinic

Systemic Lupus
Erythematosus
Screening page ITC4-2

Diagnosis page ITC4-3

Treatment page ITC4-6

Tool Kit page ITC4-14

Patient Information page ITC4-15

CME Questions page ITC4-16

Physician Writer The content of In the Clinic is drawn from the clinical information and education
Marianthi Kiriakidou MD resources of the American College of Physicians (ACP), including PIER (Physicians’
Information and Education Resource) and MKSAP (Medical Knowledge and Self-
Section Editors Assessment Program). Annals of Internal Medicine editors develop In the Clinic
Deborah Cotton, MD, MPH from these primary sources in collaboration with the ACP’s Medical Education and
Darren Taichman, MD, PhD Publishing divisions and with the assistance of science writers and physician writ-
Sankey Williams, MD ers. Editorial consultants from PIER and MKSAP provide expert review of the con-
tent. Readers who are interested in these primary resources for more detail can
consult http://pier.acponline.org, http://www.acponline.org/products_services/
mksap/15/?pr31, and other resources referenced in each issue of In the Clinic.

CME Objective: To review current evidence for the screening, diagnosis, and treat-
ment of systemic lupus erythematosus.

The information contained herein should never be used as a substitute for clinical
judgment.

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 ystemic lupus erythematosus (SLE, lupus) is a condition in which the

S immune system attacks healthy cells and tissues throughout the body.
Immune system activation in SLE is characterized by exaggerated
B-cell and T-cell responses and loss of immune tolerance against self anti-
gens. Production and defective elimination of antibodies, circulation and
1. Demas KL, Costen- tissue deposition of immune complexes, and complement and cytokine acti-
bader KH. Disparities
in lupus care and
vation contribute to clinical manifestations that range from mild fatigue and
outcomes. Curr Opin
Rheumatol.
joint pain to severe, life-threatening organ damage.
2009;21:102-9.
[PMID: 19339919] Because the symptoms of SLE vary widely and the condition often goes
2. Bernatsky S, Boivin JF,
Joseph L, et al. Mor- undiagnosed, it is unclear how many people in the United States have the
tality in systemic lu-
pus erythematosus.
disease. It is diagnosed 9 times more often in women than in men, which
Arthritis Rheum. implies pathogenic mechanisms more prevalent in women. These mecha-
2006;54:2550-7.
[PMID: 16868977] nisms, which probably involve effects of sex chromosomes, specific genes,
3. Sestak AL, Fürnrohr
BG, Harley JB, et al.
and hormones, have not been completely elucidated. SLE is more common
The genetics of sys- and more severe in African American women, Hispanic women, and those
temic lupus erythe-
matosus and implica- of other ethnic minorities (1).
tions for targeted
therapy. Ann Rheum
Dis. 2011;70 Suppl
Although there is no cure for SLE, it can be effectively managed with med-
1:i37-43. ications; however, mortality is higher in patients with SLE than in the gen-
[PMID: 21339217]
4. Deng Y, Tsao BP. Ge- eral population. The overall standardized mortality ratio (SMR) (ratio of
netic susceptibility to
systemic lupus ery-
deaths observed to deaths expected for an age group) for SLE is 2.4. Higher
thematosus in the risk for death is associated with female sex, younger age, shorter SLE dura-
genomic era. Nat Rev
Rheumatol. tion, and African American race (2).
2010;6:683-92.
[PMID: 21060334]
5. Arbuckle MR, McClain
MT, Rubertone MV, et
al. Development of
autoantibodies be-
Screening
fore the clinical onset Which patients are at elevated dysfunction in genetically predis-
of systemic lupus ery-
thematosus. N Engl J
risk for lupus? posed individuals.
Med. 2003;349:1526- Evidence to determine whether
33. [PMID: 14561795]
6. Seibold JR, Wechsler people may be at risk for lupus Should clinicians screen
LR, Cammarata RJ. LE because of specific genes is insuf- asymptomatic patients for lupus if
cells in intermittent
hydrarthrosis [Letter]. ficient. Early genetic studies, they are at increased risk?
Arthritis Rheum.
1980;23:958-9. driven by the observation of fa- Most experts do not recommend
[PMID: 6157396] milial aggregation and high con- screening asymptomatic persons
7. Ball EM, Bell AL. Lupus
arthritis—-do we cordance in monozygotic twins, for lupus, even those with a fami-
have a clinically use-
have implicated genes for HLA ly history. Nevertheless, the im-
ful classification?
Rheumatology (Ox- and early complement compo- munologic test for antinuclear
ford). 2012;51:771-9.
[PMID: 22179731] nents (3). A few rare, single-gene antibody (ANA) is often used for
8. Patel P, Werth V. Cuta- risk factors have been linked to SLE screening even though it
neous lupus erythe-
matosus: a review. SLE. For example, C1, C2, or C4 produces many false-positive re-
Dermatol Clin.
2002;20:373-85, v. genetic deficiencies can cause lu- sults. ANA is detected in 3–5% of
[PMID: 12170873] pus but account for just 1–2% of healthy individuals or patients
9. Alarcón GS, Friedman
AW, Straaton KV, et al. cases (3). Recent genome-wide with other autoimmune or infec-
Systemic lupus ery-
thematosus in three
association studies have linked tious diseases. Furthermore, sero-
ethnic groups: III. A more than 30 gene polymor- logic evidence of ANAs, which
comparison of char-
acteristics early in the phisms to lupus (4). However, the indicates immune system activa-
natural history of the functional significance of these tion, may precede the clinical
LUMINA cohort. LU-
pus in MInority popu- variants and their potential im- manifestations required for diag-
lations: NAture vs.
Nurture. Lupus. plication to SLE pathogenesis nosis by 3 to 9 years (5). No evi-
1999;8:197-209. remain largely unknown. In addi- dence suggests that treating to
[PMID: 10342712]
10. Chang AY, Werth VP. tion, sex chromosome genes, modulate the immune system
Treatment of cuta-
neous lupus. Curr
and possibly sex hormones and during this clinically “silent” peri-
Rheumatol Rep. environmental influences, may od can stop or delay lupus devel-
2011;13:300-7.
[PMID: 21503694] contribute to immune system opment.

© 2013 American College of Physicians ITC4-2 In the Clinic Annals of Internal Medicine 1 October 2013

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 Screening... Single-gene mutations causing SLE are rare. Although numerous gene
variants have been linked to lupus, current evidence is insufficient to support
screening for these variants. ANA testing in asymptomatic persons is not useful
because immune reaction to nuclear antigens is not SLE-specific, can be detected
in healthy individuals, and may precede SLE manifestations by many years.

CLINICAL BOTTOM LINE 11. Vilá LM, Alarcón GS,

McGwin G Jr, et al;
Lumina Study
Group. Systemic lu-
pus erythematosus
in a multiethnic US
Diagnosis cohort, XXXVII: asso-
ciation of lymphope-
nia with clinical
What symptoms or physical The malar rash may be confused manifestations, sero-
logic abnormalities,
examination findings should with rosacea, drug eruption, or disease activity, and
prompt clinicians to consider a polymorphous light eruption, but damage accrual.
Arthritis Rheum.
diagnosis of lupus? skin biopsy is rarely necessary when 2006;55:799-806.
The initial presentation of lupus of- other clinical manifestations and [PMID: 17013840]
12. Durán S, Apte M,
ten mimics a viral syndrome. Such serologic evidence consistent with Alarcón GS, et al; Lu-
mina Study Group.
constitutional symptoms as weight SLE are present. Subacute cuta- Features associated
loss, fatigue, and low-grade fever are neous lupus consists of annular with, and the impact
of, hemolytic anemia
common and may be accompanied lesions that may coalesce into a in patients with sys-
temic lupus erythe-
by arthralgias or arthritis. Arthritis polycyclic (overlapping ring-shaped) matosus: LX, results
in lupus is characterized by pro- rash or papulosquamous lesions from a multiethnic
cohort. Arthritis
longed morning stiffness and mild that do not scar and are distributed Rheum.
to moderate joint swelling. It is where light exposure is most fre- 2008;59:1332-40.
[PMID: 18759263]
nonerosive, may be symmetric or quent. It is often associated with 13. Bomback AS, Appel
GB. Updates on the
asymmetric, and may affect large or anti-SSA antibodies. Chronic cuta- treatment of lupus
small joints. Large effusions are not neous lupus includes discoid lupus nephritis. J Am Soc
Nephrol.
as common in lupus as in rheuma- and other rare subsets, such as lupus 2010;21:2028-35.
[PMID: 21051743]
toid arthritis, and the synovial fluid panniculitis, hypertrophic lupus ery- 14. Cervera R, Khamash-
is not as inflammatory (6). Joint thematosus (characterized by verru- ta MA, Font J, et al;
European Working
deformities are not frequent in lu- cous lesions), tumid lupus or lupus Party on Systemic
Lupus Erythemato-
pus. Jaccoud arthropathy, which tumidus (smooth, shiny, red-violet sus. Morbidity and
may include reducible ulnar devia- plaques usually on the head and mortality in systemic
lupus erythemato-
tion, swan neck deformities, or neck), and chilblain lupus (purplish- sus during a 10-year
period: a compari-
z-shaped thumb, is present in blue lesions on the fingers, toes, or son of early and late
2.8–4.3% of patients (7). When ears). Discoid lupus is the most manifestations in a
cohort of 1,000 pa-
constitutional symptoms with common form of the chronic cuta- tients. Medicine (Bal-
arthralgias or arthritis are not ac- neous disease and is characterized timore). 2003;82:299-
308.
companied by other characteristic by scarring indurated plaques that [PMID: 14530779]
15. Mok CC, Kwok RC,
manifestations of lupus, such as resolve with significant depigmenta- Yip PS. Effect of renal
photosensitive skin rash on the tion. Although acute cutaneous lu- disease on the stan-
dardized mortality
face, neck, or extremities, it is ap- pus is nearly always associated with ratio and life ex-
pectancy of patients
propriate to conduct a clinical and systemic lupus, discoid lupus is in- with systemic lupus
laboratory evaluation for infection frequently (3–5%) associated with erythematosus.
Arthritis Rheum.
before trying to establish a diagno- systemic disease (9). 2013;65:2154-60.
[PMID: 23754671]
sis of SLE. 16. Kamen DL, Strange
What other clinical manifestations C. Pulmonary mani-
Cutaneous manifestations are com- should clinicians look for in festations of sys-
temic lupus erythe-
mon and may occur in up to 70% potential cases of lupus? matosus. Clin Chest
Med. 2010;31:479-
of patients (8). They are catego- Systemic lupus may present in 88. [PMID: 20692540]
rized as acute, subacute, or chronic. many other ways. Although fever, 17. Peponis V, Kyttaris
VC, Tyradellis C, et al.
Acute cutaneous lupus consists of rash, and arthritis are the classic Ocular manifesta-
tions of systemic lu-
indurated or flat erythematous initial symptoms, abrupt onset with pus erythematosus:
lesions on the malar eminences, target-organ involvement is also a clinical review. Lu-
pus. 2006;15:3-12.
scalp, arms, hands, neck, and chest. quite common, particularly in [PMID: 16482739]

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 Hispanics (61%) and African affecting 30–50% of patients (16).
Americans (45%), as compared Lupus pleuritis should be diag-
with white patients (41%) (10). nosed only after an analysis of
18. Hochberg MC. Up-
dating the American
SLE should be considered when pleural fluid and an evaluation for
College of Rheuma- patients, particularly women of re- other causes of pleural effusion,
tology revised crite-
ria for the classifica- productive age, present with hema- such as infection, pulmonary em-
tion of systemic
lupus erythemato-
tologic, renal, respiratory, or central bolism, liver disease, heart disease,
sus [Letter]. Arthritis nervous system (CNS) manifesta- and cancer. Bronchoscopy for bac-
Rheum.
1997;40:1725. tions, especially hematologic find- terial, mycobacterial, fungal, and viral
[PMID: 9324032] ings, such as thrombocytopenia, cultures may be indicated. Vascular
19. Petri M, Orbai AM,
Alarcón GS, et al. leukopenia, lymphopenia, or ane- involvement may cause diffuse
Derivation and vali-
dation of the Sys- mia; renal findings, such as hema- alveolar hemorrhage, pulmonary
temic Lupus Interna- turia, proteinuria, cellular casts, or hypertension, or thromboembolic
tional Collaborating
Clinics classification elevated serum creatinine; respira- disease. Parenchymal damage is less
criteria for systemic
lupus erythemato-
tory symptoms, such as cough, dys- common and may be the result of
sus. Arthritis Rheum. pnea, hemoptysis, or pleuritic pain; interstitial lung disease, acute pneu-
2012;64:2677-86.
[PMID: 22553077] or CNS signs, such as headache, monitis, or bronchiolitis obliterans
20. Sun S, Rao NL, Ven-
able J, Thurmond R,
photophobia, or focal neurologic with organizing pneumonia. Acute
Karlsson L. TLR7/9 deficits. lupus pneumonitis is rare and car-
antagonists as thera-
peutics for immune- ries a high mortality risk. Infection
mediated inflamma- Hematologic manifestations and pulmonary embolism must al-
tory disorders.
Inflamm Allergy Cytopenias are common in patients ways be excluded in patients with
Drug Targets. with lupus, and moderate-to-severe suspected lupus pneumonitis.
2007;6:223-35.
[PMID: 18220957] lymphopenia is associated with
21. Ben-Zvi I, Kivity S,
Langevitz P, Shoen-
high disease activity and organ Neuropsychiatric manifestations
feld Y. Hydroxy- damage (11). Hemolytic anemia is Neuropsychiatric SLE manifesta-
chloroquine: from
malaria to autoim- uncommon and usually associated tions may be caused by vasculopathy,
munity. Clin Rev Al-
lergy Immunol.
with disease onset, thrombocy- autoantibodies, and inflammatory
2012;42:145-53. topenia, and African American mediators and include headache,
[PMID: 21221847]
22. Farrell DF. Retinal ethnicity (12). aseptic meningitis, vasculitis, move-
toxicity to antimalar-
ial drugs: chloro-
ment disorder, seizure disorder,
quine and hydroxy- Renal manifestations cognitive dysfunction, psychosis,
chloroquine: a
neurophysiologic
Renal involvement is a common demyelinating disease, myelopathy,
study. Clin Ophthal- target-organ manifestation; it has autonomic disorder, and peripheral
mol. 2012;6:377-83.
[PMID: 22457587] a poor prognosis due to the high neuropathy.
23. Mackworth-Young risk for organ failure. Up to
CG, David J, Morgan
SH, et al. A double 50% of SLE patients have some Ocular manifestations
blind, placebo con-
trolled trial of intra-
evidence of renal disease at presen- Ocular manifestations include kera-
venous methylpred- tation (13). SLE nephritis is asso- toconjuctivitis sicca (with or without
nisolone in systemic
lupus erythemato- ciated with a worse prognosis for the Sjogren syndrome), keratitis,
sus. Ann Rheum Dis.
1988;47:496-502.
10-year survival than the nonrenal episcleritis, scleritis, uveitis, retinal
[PMID: 3289511] disease (14). Compared with the vasculitis, occlusion of the retinal
24. Albert DA, Hadler
NM, Ropes MW. general population, life expectancy artery or vein, retinopathy, and nu-
Does corticosteroid
therapy affect the
is reduced by 12.4, 15.1, and 23.7 merous other less common mani-
survival of patients years in lupus patients, those with festations (17).
with systemic lupus
erythematosus? renal disease, and those with renal
Arthritis Rheum. damage, respectively (15). Gastrointestinal manifestations
1979;22:945-53.
[PMID: 475873] Gastrointestinal symptoms may
25. Edwards JC, Snaith Respiratory involvement include anorexia, nausea, vomit-
ML, Isenberg DA. A
double blind con- Involvement of the respiratory sys- ing, abdominal pain, and diarrhea.
trolled trial of
methylprednisolone
tem may be primary or secondary. Other causes of abdominal pain in
infusions in systemic Presenting symptoms and the re- lupus are mesenteric vasculitis and
lupus erythemato-
sus using individu- sponse to treatment vary, depend- hepatobiliary disease. Rare gas-
alised outcome as-
sessment. Ann
ing on the affected anatomical site. trointestinal complications include
Rheum Dis. Pleuritis is the most common intestinal pseudo-obstruction,
1987;46:773-6.
[PMID: 3318723] respiratory SLE manifestation, protein-losing enteropathy, and

© 2013 American College of Physicians ITC4-4 In the Clinic Annals of Internal Medicine 1 October 2013

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 pancreatitis. Immunocompromised diagnosing SLE, based on objective
lupus patients are also prone to disease manifestations. However,
enteritis from cytomegalovirus or patients with mild disease may be
salmonella infection. missed. In 2012 the Systemic Lu-
pus International Collaborating
Lupus is a multiorgan disease that Clinics revised the ACR classifica-
can mimic infectious diseases, can- tion criteria, increasing the sensitiv- 26. Badsha H, Kong KO,
Lian TY, et al. Low-
cer, and other autoimmune condi- ity but not the specificity of dose pulse methyl-
tions. Table 1 lists the American detecting SLE compared with the prednisolone for sys-
temic lupus
College of Rheumatology (ACR) 1997 ACR criteria (19). erythematosus flares
classification criteria for SLE (18). is efficacious and
has a decreased risk
These criteria facilitate a systemat- What laboratory tests should of infectious compli-
cations. Lupus.
ic approach to diagnosis by focus- clinicians use to diagnose lupus? 2002;11:508-13.
ing on the most common SLE Clinicians should test for ANA, [PMID: 12220105]
27. Buttgereit F, da Silva
manifestations. Four of the 11 cri- and if the result is positive, follow- JA, Boers M, et al.
Standardised
teria are required for classification up testing for antigen-specific nomenclature for
of systemic lupus. Although in- ANAs, such as those targeting glucocorticoid
dosages and gluco-
tended to assist in classification, double-stranded DNA (dsDNA) or corticoid treatment
the ACR criteria offer a highly ribonucleoprotein complexes regimens: current
questions and tenta-
sensitive and specific tool for (Ro/SSA, La/SSB, Smith, and tive answers in
rheumatology. Ann
Rheum Dis.
2002;61:718-22.
Table 1. American College of Rheumatology Classification Criteria for SLE* [PMID: 12117678]
28. Da Silva JA. Safety of
Criterion Definition glucocorticoids -
clinical trials. Clin
Malar rash Flat or raised erythema over the malar eminences, sparing the nasolabial folds Exp Rheumatol.
2011;29:S99-103.
Discoid rash Erythematous raised patches or atrophic scarring (older lesions) [PMID: 22018193]
29. Carneiro JR, Sato EI.
Double blind, ran-
Photosensitivity Skin rash as a result of unusual reaction to sunlight domized, placebo
controlled clinical
trial of methotrexate
Oral ulcers Usually painless oral or nasopharyngeal ulcerations, observed by physician in systemic lupus
erythematosus. J
Arthritis Nonerosive arthritis, involving 2 or more peripheral joints characterized by tenderness and Rheumatol.
swelling 1999;26:1275-9.
[PMID: 10381042]
30. Islam MN, Hossain
Serositis Pleuritis: Convincing history of pleuritic pain or rubbing heard by physician, or evidence of M, Haq SA, et al. Effi-
pleural effusion cacy and safety of
methotrexate in ar-
Pericarditis: Documented by electrocardiogram, or rub or evidence of pericardial effusion ticular and cuta-
neous manifesta-
Renal disorder Persistent proteinuria >0.5 g/d or >3 on dipstick tions of systemic
lupus erythemato-
Cellular casts red cell, hemoglobin, granular, tubular, or mixed sus. Int J Rheum Dis.
2012;15:62-8.
Neurologic disorder Seizures (in the absence of offending drugs or metabolic derangement) [PMID: 22324948]
31. Fortin PR, Abra-
Psychosis (in the absence of offending drugs or metabolic derangement) hamowicz M, Fer-
land D, et al; Canadi-
an Network For
Hematologic disorder Hemolytic anemia: with reticulocytosis Improved Outcomes
Leukopenia: <4000/mm on 2 or more occasions in Systemic Lupus.
Steroid-sparing ef-
Lymphopenia: <1500/mm on 2 or more occasions fects of methotrex-
Thrombocytopenia: <100 000/mm in the absence of offending drugs ate in systemic lupus
erythematosus: a
double-blind, ran-
Immunologic disorder Anti-DsDNA domized, placebo-
controlled trial.
Anti-Smith antibodies Arthritis Rheum.
Antiphospholipid antibodies based on an abnormal serum level of IgG or IgM anticardiolipin 2008;59:1796-804.
antibodies, positive test result for lupus anticoagulant using a standard method, or false- [PMID: 19035431]
32. Gourley MF, Austin
positive serologic test result for syphilis known to be positive for at least 6 mo and confirmed HA 3rd, Scott D, et al.
as false-positive by Treponema pallidum immobilization or fluorescent treponemal antibody Methylprednisolone
absorption tests and cyclophos-
phamide, alone or in
combination, in pa-
Antinuclear antibody Detected by immunofluoresence (or equivalent assay) in the absence of drugs known to be tients with lupus
associated with drug-induced SLE nephritis. A random-
ized, controlled trial.
Ann Intern Med.
*From reference 18. 1996;125:549-57.
[PMID: 8815753]

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 RNP, which are collectively referred extractable nuclear antigens, are rare
Basic Investigations for SLE
to as extractable nuclear antigens) in drug-induced lupus, and symp-
Complete blood count
should be done. The specificity of toms usually abate within days or
Direct Coombs test (indicated if
patients present with hemolytic anti ds-DNA antibodies for lupus is weeks after drug discontinuation.
anemia and reticulocytosis) >60%. Anti-Smith antibodies are
Comprehensive metabolic panel >90% specific for lupus; however, Small- or medium-vessel vasculitides,
Erythrocyte sedimentation rate they are detected in only about 30% thrombotic thrombocytopenic pur-
C-reactive protein of lupus patients. The initial labora- pura, and viral arthritis, as seen in
Urinalysis tory evaluation to assess disease ac- parvovirus infection and HIV/AIDS,
Serologic testing (ANA and if tivity and target-organ involvement can also mimic SLE. Differential di-
positive, anti-DsDNA, anti-
SSA/SSB, anti-Smith/RNP anti- is described in the Box (Basic Inves- agnosis relies on laboratory studies,
phospholipid antibodies); a tigations for SLE). detection of viral serologies, and tis-
negative ANA test is inconsistent sue histopathology. Hematopoietic
with the diagnosis of SLE What other diagnoses should
Complement C3 and C4
cancer and malignant lymphoprolif-
clinicians consider? erative syndromes may present with
Creatine phosphokinase (indicated The chronic fatigue syndrome and fi-
in patients presenting with positive ANA, anemia, low-grade
muscle weakness) bromyalgia may present with diffuse fever, pleural effusions, and lym-
musculoskeletal symptoms mimick-
phadenopathy and can be misdiag-
ing lupus, or may be secondary to
nosed as lupus.
33. Illei GG, Austin HA,
Crane M, et al. Com-
SLE. SLE can be excluded in the ab-
bination therapy sence of inflammatory pain and neg- When should clinicians consider
with pulse cy-
clophosphamide ative results on serologic evaluation. consulting with a rheumatologist
plus pulse methyl-
prednisolone im-
Rheumatoid arthritis is characterized or other specialist for diagnosing
proves long-term re- by symmetric, intensely inflammatory, patients with possible lupus?
nal outcome
without adding toxi- erosive arthritis (when advanced) and Clinicians should consult a
city in patients with positive results on rheumatoid factor rheumatologist in all patients when
lupus nephritis. Ann
Intern Med. or anti-CCP antibody testing. clinical manifestations and serolog-
2001;135:248-57.
[PMID: 11511139]
Such drugs as procainamide, hy- ic studies suggest SLE. Evidence of
34. Hochstadt A, Roz-
man Z, Zandman- dralazine, minocycline, isoniazide, renal, pulmonary, CNS, ocular, or
Goddard G. [My-
cophenolate mofetil and tumor necrosis factor inhibitors gastrointestinal disease necessitates
as a novel treatment
for lupus nephritis]. can cause drug-induced lupus, a clin- a coordinated, multidisciplinary ap-
Harefuah. ical syndrome resembling SLE char- proach with the help of appropriate
2011;150:542-7, 550.
[PMID: 21800496] acterized by fever, serositis, arthritis, specialists. The goal of care is a
35. Anderka MT, Lin AE, timely, accurate diagnosis; effective
Abuelo DN, et al. Re- and rash. Antihistone antibodies are
viewing the evi- detected in approximately 75% of pa- treatment of acute disease; appro-
dence for mycophe-
nolate mofetil as a tients; however, they can also be seen priate monitoring and dose adjust-
new teratogen: case
report and review of
in SLE and are not pathognomonic. ment; and early introduction of a
the literature. Am J Anti-dsDNA, or antibodies to steroid-sparing regimen.
Med Genet A.
2009;149A:1241-8.
[PMID: 19441125]
36. Kamanamool N,
McEvoy M, Attia J, et Diagnosis... Lupus is a multisystem disease that often presents as a diagnostic chal-
al. Efficacy and ad-
verse events of my-
lenge because it can include cutaneous, renal, respiratory, cardiovascular, CNS, and
cophenolate mofetil gastrointestinal manifestations that characterize numerous other conditions. The ACR
versus cyclophos- classification criteria can be used to guide the diagnosis of systemic lupus.
phamide for induc-
tion therapy of lupus
nephritis: systematic
review and meta-
analysis. Medicine
CLINICAL BOTTOM LINE
(Baltimore).
2010;89:227-35.
[PMID: 20616662]
37. Touma Z, Gladman
DD, Urowitz MB, et
al. Mycophenolate
mofetil for induction
Treatment
treatment of lupus
nephritis: a system- What medications are used to glucocorticoids, antimalarial agents,
atic review and
metaanalysis. J
treat lupus? and nonsteroidal anti-inflammatory
Rheumatol. Clinicians use a broad range of med- drugs (NSAIDs) (Table 2). Hydroxy-
2011;38:69-78.
[PMID: 20952473] ications to treat lupus, including chloroquine prevents disease flares

© 2013 American College of Physicians ITC4-6 In the Clinic Annals of Internal Medicine 1 October 2013

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 Table 2. Drug Treatment for SLE
Agent Mechanism of Action Dosage Common Side Effects
NSAIDs Anti-inflammatory Gastritis, nephrotoxicity, fluid retention

Glucocorticoids Anti-inflammatory effect Low: ≤7 mg/d; medium: Fluid retention, diabetes mellitus,
due to negative transcriptional >7–≤30 mg/d; high: >30– hypertension, acne, myopathy,
regulation of pro-inflammatory ≤ 100 mg/d; very high: hyperlipidemia, psychosis, avascular bone
genes >100 mg/d; pulse: 250 mg/d (27) necrosis, osteoporosis

Hydroxychloroquine Immunomodulatory and 200–400 mg/d (orally) Skin hyperpigmentation, retinal toxicity
antithrombotic effect (rare), myopathy with peripheral
neuropathy and cardiac myotoxicity
(extremely rare)

Mycophenolate mofetil
Inhibits lymphocyte proliferation Up to 3000 mg/d (orally) Gastrointestinal intolerance, myelosup-
by inhibiting inosine monophosphate pression
dehydrogenase and de novo synthesis
of guanosine nucleotides; promotes
apoptosis of T-lymphocytes

Azathioprine Metabolizes to 6-TG and 6-MMP 50–150 mg/d (orally) Gastrointestinal intolerance, myelosup-
and inhibits DNA synthesis and cell pression, hepatotoxicity
proliferation

Methotrexate Inhibits DNA synthesis and increases 5–25 mg/wk (orally or sub- Gastrointestinal intolerance, hepatotoxicity
release of adenosine cutaneously)

Cyclophosphamide Alkylating agent, promotes DNA Based on body surface area Hair loss, gastrointestinal toxicity, myelo-
cross-linking and inhibits T- and and renal function (IV or oral suppression, hemorrhagic cystitis, bladder
B-lymphocyte proliferation administration) cancer, gonadal suppression, infertility

Cyclosporine Calcineurin inhibitor inhibits 2.5–4.5 mg/kg/d (orally) Nephrotoxicity, interaction with allopurinol,
T-lymphocyte proliferation and hypertension, myelosuppression
expression or activation of pro-
inflammatory cytokines

Tacrolimus Calcineurin inhibitor 2–3 mg/d (orally) Nephrotoxicity, neurotoxicity, myocardial

hypertrophy, hyperkalemia, infection, cancer

Belimumab Targets B-lymphocyte stimulator, Three 10 mg/kg doses given IV at Hypersensitivity reaction, gastrointestinal
inhibits B-lymphocyte proliferation 2-wk intervals and then 10 mg/kg toxicity, myalgias, depression, migraine,
and activation IV every mo infection

Rituximab Depletes CD20-expressing Two 1000 mg doses given IV at Infusion reaction, infection, progressive
B-lymphocytes 2-wk intervals; may be repeated multifocal leukoencephalopathy (rare)
every 6 mo

and is considered the cornerstone of immunosuppressive therapy and a

SLE treatment. Glucocorticoids are multidisciplinary approach.
first-line agents for most SLE mani-
festations, with dosage and treatment How should clinicians initiate
38. Hahn BH, McMahon
duration based on clinical experience therapy in a stable patient who is MA, Wilkinson A, et
al; American College
and consensus. Immunosuppressive not having a flare? of Rheumatology.
treatment in lupus nephritis is based Hydroxychloroquine and other an- American College of
Rheumatology
on histopathologic classifications. timalarial agents have been used to guidelines for
screening, treat-
Treatment of other lupus manifes- treat inflammatory arthritides for ment, and manage-
tations is based on sparse evidence at least 50 years (20). In addition ment of lupus
nephritis. Arthritis
from clinical trials and clinical to preventing lupus relapses and Care Res (Hoboken).
2012;64:797-808.
experience and often requires reducing the risk for congenital [PMID: 22556106]

1 October 2013 Annals of Internal Medicine In the Clinic ITC4-7 © 2013 American College of Physicians

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 heart block in neonatal SLE, hy- 3 daily doses of 100 mg (25). A more recent
droxychloroquine has antithrom- randomized study showed that a dose of
botic effects that are particularly 1000 mg to 1500 mg over 3 days is as ef-
important to SLE patients with fective as doses ranging from 2000 mg to
antiphospholipid antibody-related 5000 mg over 3 days and is associated
with a decreased risk for infections (26).
prothrombotic diathesis (21). Hy-
droxychloroquine is generally well- Significant overlap exists between
39. Contreras G, Pardo V,
Leclercq B, et al. Se- tolerated, and the rare risk for lupus manifestations and some
quential therapies retinopathy is directly related to
for proliferative lu- glucocorticoid complications, in-
pus nephritis. N Engl the years of exposure to the drug cluding osteoporosis, avascular
J Med. 2004;350:971-
80. [PMID: 14999109] and the age of the patient. bone necrosis, myopathy, and psy-
40. Dooley MA, Jayne D,
Ginzler EM, et al; In a study of 29 cases of antimalarial reti-
chosis. Furthermore, despite the
ALMS Group. My-
cophenolate versus nal toxicity over a period of 30 years, all abundance of observational data
azathioprine as patients were older than 40 years and on glucocorticoid toxicity, evidence
maintenance thera-
py for lupus nephri- had had exposure to the agents over from randomized, controlled clini-
tis. N Engl J Med. 5 years (22). cal trials (RCTs) is limited. Table 2
2011;365:1886-95.
[PMID: 22087680] summarizes the 2002 European
41. Houssiau FA, D’Cruz Skin hyperpigmentation and rare League Against Rheumatism rec-
D, Sangle S, et al;
MAINTAIN Nephritis cases of neuromuscular or cardiac ommendations on glucocorticoid
Trial Group. Azathio-
prine versus my-
toxicity have also been reported. treatment (27). These recommen-
cophenolate mofetil dations define a low daily dose of
for long-term im-
munosuppression in
How should clinicians choose prednisone (or equivalent) as ≤7 mg.
lupus nephritis: re- therapy for a patient who is Low doses are associated with rela-
sults from the MAIN-
TAIN Nephritis Trial.
having a flare? tively low risk for toxicity, although
Ann Rheum Dis. Severe SLE manifestations, such as monitoring for cushingoid symp-
2010;69:2083-9.
[PMID: 20833738] lupus nephritis, alveolar hemor- toms, osteoporosis, cataracts,
42. Moroni G, Doria A, rhage, or CNS vasculitis, should be
Mosca M, et al. A glaucoma, hyperglycemia, and hy-
randomized pilot tri- treated with glucocorticoids admin- pertension is probably justified.
al comparing cy-
closporine and aza- istered intravenously (IV) in con- Prolonged treatment with medium
thioprine for
maintenance thera-
junction with immunosuppressive to high doses carries a higher risk
py in diffuse lupus medications. Glucocorticoids can be for complications, including my-
nephritis over four
years. Clin J Am Soc gradually withdrawn once remission opathy, psychosis, hyperlipidemia,
Nephrol. 2006;1:925- is achieved. Oral prednisone or and atherosclerosis. However, the
32. [PMID: 17699309]
43. Lee YH, Lee HS, Choi methlyprednisolone is used for prevalence and incidence of these
SJ, et al. Efficacy and
safety of tacrolimus
arthritis, pleuropericarditis, cuta- complications in different corti-
therapy for lupus neous vasculitis, and uveitis. costeroid regimens are still un-
nephritis: a system-
atic review of clinical
trials. Lupus. Early studies demonstrated that clear (28).
2011;20:636-40.
[PMID: 21382917]
glucocorticoids could ameliorate How should clinicians choose drug
44. Merrill JT, Neuwelt SLE, although subsequent con- therapy for cutaneous mani-
CM, Wallace DJ, et al.
Efficacy and safety of trolled trials showed that the thera- festations?
rituximab in moder- peutic effect was not sustained (23).
ately-to-severely ac- Commonly used topical treatments
tive systemic lupus Early studies also linked glucocorti- for all forms of cutaneous lupus
erythematosus: the
randomized, double- coids to improved survival in severe (acute, subacute, and chronic)
blind, phase II/III sys-
temic lupus erythe-
SLE (24), but similar studies have include tacrolimus, R-salbutamol
matosus evaluation not been done for mild or moderate pimecrolimus, clobetasol, betametha-
of rituximab trial.
Arthritis Rheum. disease. Current decisions about sone, or photoprotection. Their effi-
2010;62:222-33. glucocorticoid dosage and the cacy has been shown by RCTs. Such
[PMID: 20039413]
45. Rovin BH, Furie R, La- duration of treatment for specific trials have also shown efficacy of sys-
tinis K, et al; LUNAR
Investigator Group.
manifestations rely largely on clini- temic hydroxychloroquine or chloro-
Efficacy and safety of cal experience because too few clin- quine in cutaneous SLE. Although
rituximab in patients
with active prolifera- ical trials have been done. other immunosuppressive or biologic
tive lupus nephritis:
the Lupus Nephritis An early study comparing 100 mg agents, such as methotrexate, my-
Assessment with Rit-
uximab study. Arthri- with 1000 mg of IV methylprednisolone cophenolate mofetil, azathioprine,
tis Rheum. suggested that 3 daily doses of 1000 mg and rituximab, may be used for cuta-
2012;64:1215-26.
[PMID: 22231479] did not have a significant advantage over neous lupus, evidence is based on

© 2013 American College of Physicians ITC4-8 In the Clinic Annals of Internal Medicine 1 October 2013

Downloaded From: http://annals.org/ by a Harvard Medical School User on 10/06/2013

 case reports or prospective, nonran-
domized studies (9).
How should clinicians choose drug
therapy for lupus arthritis?
Low-dose glucocorticoids and
antimalarials are first-line agents
for treating arthritis in lupus.
Methotrexate is often used for
arthritis or cutaneous disease, par-
ticularly in patients without other
systemic manifestations.
A double-blind RCT showed that methotrex-
ate is effective in controlling cutaneous and
articular symptoms in SLE (29). These find-
ings were also supported by a recent open-
label trial (30) and an RCT showing that
methotrexate can be used as a steroid-
sparing agent in SLE (31).
Methotrexate antagonizes folic acid
and inhibits purine and pyrimidine
synthesis. In addition, it increases
extracellular adenosine release.
Adenosine seems to be an important
mediator of the anti-inflammatory
effect of methotrexate.
How should clinicians choose and
dose drug therapy for lupus
nephritis?
Induction therapy
The indications for kidney biopsy
are in the Box: Indications for Kid-
ney Biopsy in Patients With SLE;
the currently accepted classification
system for biopsy results are in the
Box: Histopathologic Classification
of Lupus Nephritis.
Class I or II lupus nephritis does
not require immunosuppressive
therapy. Class III or IV is treated
aggressively. Until recently, cyclo-
phosphamide combined with intra-
venous glucocorticoids has been
the standard of care for induction
therapy of class III and IV lupus
nephritis. Cyclophosphamide is
an alkylating agent that promotes
DNA cross-linking and affects T-
and B-cell proliferation and anti-
body production. It is usually dosed
according to total body surface area
and adjusted for decreased creati-
nine clearance. Cyclophosphamide
1 October 2013 Annals of Internal Medicine
Downloaded From: http://annals.org/ by a Harvard Medical School User on 10/06/2013
toxicity includes hematologic, in-
Indications for Kidney Biopsy in
fectious, urologic, reproductive, and
Patients With SLE*
rare pulmonary complications and
Increasing serum creatinine without
bladder, skin, myeloproliferative, compelling alternative causes
and oropharyngeal cancers. To date, Confirmed proteinuria ≥1.0 g/24 h
there is no definitive evidence from (either 24-h urine specimens or
clinical trials to guide clinicians on spot protein–creatinine ratio)
the dose of glucocorticoids for in- Combination of the following:
Proteinuria ≥0.5 ≥1.0 g/24 h +
duction therapy of lupus nephritis. hematuria (≥5 red blood
Current ACR recommendations cells/high-power field) or
are based on expert opinion and proteinuria ≥0.5 ≥1.0 g/24 h +
consensus. cellular casts
* From reference 38.
Early open-label trials and RCTs showed
short-term efficacy of glucocorticoids for
treatment of lupus nephritis. Subsequently, Histopathologic Classification of
an RCT comparing cyclophosphamide to Lupus Nephritis
glucocorticoids showed superiority of cy- Class I: Minimal mesangial
clophosphamide for induction therapy of Class II: Mesangial proliferative
proliferative lupus nephritis. Nonresponse Class III: Focal proliferative
was more common in the group treated with Class IV: Diffuse proliferative (with
IV glucocorticoids and the probability of active, active and chronic, or
achieving remission was higher in the gluco- chronic lesions)
corticoid plus cyclophosphamide group (32). Class V: Membranous (with or
without coexisting class III or IV
Long-term follow-up of the study partici- lupus nephritis)
pants indicated that an increase in creatinine Class VI: Advanced sclerosing lupus
nephritis with >90% globally
by 50% or 100% was less common in patients
sclerotic glomeruli
receiving combination treatment (33).
Over the past decade, several studies
have shown efficacy of mycophenolate
mofetil for induction therapy in lupus
nephritis (34–36). This drug is metab-
olized to mycophenolic acid, an in-
hibitor of inosine 5-monophosphate
dehydrogenase, which is required for
de novo synthesis of guanosine nu-
cleotides. Mycophenolate mofetil 46. Andrade-Ortega L,
inhibits lymphocyte proliferation, Irazoque-Palazuelos
F, López-Villanueva
induces apoptosis of activated T-cells, R, et al. [Efficacy of
rituximab versus cy-
and inhibits adhesion molecule ex- clophosphamide in
pression and fibroblast proliferation. lupus patients with
severe manifesta-
Gastrointestinal toxicity is common tions. A randomized
and multicenter
and may respond to dose reduction study]. Reumatol
or enteric-coated formulation. Clin. 2010;6:250-5.
[PMID: 21794725]
Hematologic toxicity is also com- 47. Radhakrishnan J,
Moutzouris DA, Gin-
mon, ranging from mild cytopenias zler EM, et al. My-
to red cell aplasia. Mycophenolate cophenolate mofetil
and intravenous cy-
mofetil is contraindicated in preg- clophosphamide are
similar as induction
nancy because of case reports sug- therapy for class V
gesting teratogenicity (37). lupus nephritis. Kid-
ney Int. 2010;77:152-
In a meta-analysis of 4 selected RCTs eval-
60. [PMID: 19890271]
48. Spetie DN, Tang Y,
uating the efficacy of mycophenolate Rovin BH, et al. My-
cophenolate therapy
mofetil vs. cyclophosphamide for induction of SLE membranous
therapy, when data on maintenance thera- nephropathy. Kidney
Int. 2004;66:2411-5.
py were excluded mycophenolate mofetil [PMID: 15569333]
In the Clinic ITC4-9 © 2013 American College of Physicians
 was not superior to cyclophosphamide in
lupus nephritis (36).
Recently updated guidelines rec-
ommend using either cyclophos-
phamide or mycophenolate mofetil
combined with glucocorticoids for
induction therapy of class III or
IV proliferative lupus nephritis
(38). Response to cyclophos-
phamide or mycophenolate mofetil
may differ based on race. Asians
and Europeans seem to respond
better to cyclophosphamide than
Hispanics and African Americans
(38).
Maintenance therapy
Current guidelines recommend
either mycophenolate mofetil or aza-
thioprine for maintenance therapy in
lupus nephritis. Both are superior to
cyclophosphamide for this purpose
(39). Evidence from 2 studies of
comparative efficacy of mycopheno-
late mofetil vs. azathioprine is con-
flicting (40, 41). Treatment duration
is guided by clinical experience.
In a study of 227 patients with lupus nephri-
tis class III, IV, or V who showed a clinical re-
sponse to a 24-week induction with either
cyclophosphamide or mycophenolate
mofetil, patients were randomly assigned to
treatment with mycophenolate mofetil
(2 g/d) or azathioprine (2 mg/kg/d). After 3
years of follow up, mycophenolate mofetil
was significantly superior to azathioprine
with respect to time to treatment failure (pri-
mary end point), time to renal flare, and
time to rescue therapy (40).
In contrast, an open-label study showed
no significant difference in patients treated
with mycophenolate mofetil vs. azathio-
prine for maintenance treatment of lupus
nephritis over a period of 4 years. All
patients in the study were initially treated
with low-dose cyclophosphamide for in-
duction therapy (41).
Calcineurin inhibitors, such as cy-
closporine, are also used for mainte-
nance therapy.
A multicenter, randomized, open pilot trial
compared the efficacy of cyclosporine vs.
azathioprine for maintenance therapy of
lupus nephritis. Seventy-five patients with
© 2013 American College of Physicians
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lupus nephritis IV, Vc, or Vd, initially treated
with IV glucocorticoids (1 mg/kg/3 d) fol-
lowed by oral cyclophosphamide and pred-
nisone for a median of 90 days, were
randomized to treatment with azathioprine
or cyclosporine for 2 (core study) and 4
years. Azathioprine and cyclosporine were
equally effective in preventing disease flares,
the primary outcome of the study. Protein-
uria, a secondary end point, decreased sig-
nificantly with both treatments. Blood
pressure and creatinine clearance did not
change significantly with either treatment;
extrarenal manifestations and clinical ac-
tivity decreased with both treatments (42).
Data from this study indicate that
cyclosporine and azathioprine are
equally effective for maintenance
treatment of lupus nephritis and
have similar effects on blood pres-
sure and renal function.
Tacrolimus, also a calcineurin in-
hibitor, may be used to treat diffuse
proliferative or membranous lupus
nephritis. Meta-analysis of data
from open-label trials, case–control
studies, and RCTs showed that
tacrolimus may be effective as in-
duction and maintenance therapy
for lupus nephritis or in treatment
of refractory lupus nephritis with
persistent proteinuria (43).
Rituximab is a monoclonal antibody
directed against CD20, a membrane
protein expressed on B-cells. Ritux-
imab depletes B-cells from the pe-
ripheral blood. Open-label trials
indicated improvement of lupus
nephritis after B-cell depletion; how-
ever, RCTs did not show statistically
significant response compared with
placebo (44–46).
Current ACR guidelines propose
mycophenolate mofetil or azathio-
prine as preferred maintenance thera-
py for proliferative lupus nephritis.
Calcineurin inhibitors or rituximab
combined with glucocorticoids may
be used for patients with an adequate
response to cyclophosphamide or
mycophenolate mofetil (38). To date,
no RCT has directly compared cal-
cineurin inhibitors to mycophenolate
ITC4-10 In the Clinic
mofetil for maintenance treatment of
class III or IV lupus nephritis.
How should clinicians choose drug
therapy for membranous nephritis?
Pure membranous nephritis is not
associated with endocapillary pro-
liferation and presents with variable
degrees of proteinuria. The pro-
gression of renal dysfunction is
slow compared with that of class
III or IV lupus nephritis. The evi-
dence to guide treatment of mem-
branous lupus nephritis is limited.
A retrospective analysis of 2 large RCTs
showed similar efficacy of mycophenolate
mofetil and cyclophosphamide for induc-
tion therapy of class V lupus nephritis (47).
A prospective study of mycophenolate
mofetil combined with renoprotective ther-
apy (with angiotensin inhibitors or an-
giotensin-receptor blockers) showed that
most patients achieved complete or partial
remission at 6 months and sustained effect
for a mean follow-up of 18 months (48).
Based on this evidence, current
guidelines from the ACR for mem-
branous lupus nephritis recommend
treatment with mycophenolate
mofetil. Tacrolimus and azathio-
prine have also been studied for in-
duction or maintenance treatment.
A recent open-label trial showed that
tacrolimus or mycophenolate mofetil com-
bined with steroids were both effective in con-
trolling membranous lupus nephritis (49).
An RCT comparing azathioprine with
tacrolimus, both combined with pred-
nisone, for maintenance therapy of mem-
branous nephritis suggests similar low
rates in relapse with both regimens (50).
How should clinicians choose
therapy for neuropsychiatric
lupus?
Treatment of serious neuropsychi-
atric SLE manifestations is rela-
tively empirical and includes IV
glucocorticoids, immunoglobulin,
and cyclophosphamide.
An RCT comparing cyclophosphamide
with glucocorticoids after 3 days of IV im-
munoglobulin for treatment of transverse
Annals of Internal Medicine 1 October 2013
 myelitis in lupus showed that relapse was
more common in the steroid group (51).
Case reports and small, uncon-
trolled studies suggest a beneficial
effect of rituximab in treatment of
neuropsychiatric lupus; however,
the relapse rate seems to be high.
How should clinicians choose
therapy for respiratory
manifestations?
Pleuritis responds to treatment with
NSAIDs and low to moderate dos-
es of glucocorticoids. Immunosup-
pressive treatment is reserved for
refractory cases. Diffuse alveolar
Azathioprine or cyclophosphamide
is frequently recommended for pa-
tients who have not responded to
glucocorticoids (56). Acute lupus
pneumonitis requires treatment
with high doses of glucocorticoids
and cyclophosphamide.
How should clinicians choose 49. Yap DY, Yu X, Chen
XM, et al. Pilot 24
therapy for ocular manifestations? month study to
compare mycophe-
Depending on the severity of the
nolate mofetil and
ocular involvement and the activity tacrolimus in the
treatment of mem-
of the systemic disease, treatment branous lupus
may include antimalarial agents, nephritis with
nephrotic syndrome.
NSAIDs, or oral or IV glucocorti- Nephrology (Carl-
ton). 2012;17:352-7.
coids. Scleral or retinal involvement
[PMID: 22295934]

hemorrhage presents abruptly, car- may require concomitant use of 50. Chen W, Liu Q, Chen
W, et al. Outcomes
ries a poor prognosis, and requires pulse glucocorticoids, followed by of maintenance
therapy with
treatment with IV glucocorticoids 1 mg/kg of prednisone equivalent, tacrolimus versus

and immunosupressants. Plasma- combined with immunosuppressive azathioprine for ac-

tive lupus nephritis:
pheresis may also be considered. therapy (57). Retinal vasculitis and a multicenter ran-
domized clinical trial.
Pulmonary hypertension is rare in arterial or venous retinal occlusion Lupus. 2012;21:944-

SLE (0.5–17%) and may be sec- in the presence of antiphospholipid 52. [PMID: 22438027]
51. Kovacs B, Lafferty TL,
ondary to vasculopathy, interstitial antibodies may require concomitant Brent LH, et al. Trans-
verse myelopathy in
pulmonary fibrosis, or in situ use of immunosuppressive medica- systemic lupus ery-
thrombosis (52). SLE patients with tions and antiplatelet agents or an- thematosus: an
analysis of 14 cases
pulmonary hypertension are at high ticoagulation. and review of the lit-
erature. Ann Rheum
risk for cardiac failure and early Dis. 2000;59:120-4.
What new medications are [PMID: 10666167]
death. Endothelin-receptor antago-
available for treating systemic 52. Dhala A. Pulmonary
nists, phosphodiesterase-5 in- arterial hypertension
lupus? in systemic lupus
hibitors, and prostacyclin analogs erythematosus: cur-
A monoclonal antibody targeting rent status and fu-
with or without immunosuppressive
the B-lymphocyte stimulator ture direction. Clin
medications may be used to treat Dev Immunol.
(BLys) was recently approved. 2012;2012:854941.
pulmonary hypertension in lupus. [PMID: 22489252]
53. Gonzalez-Lopez L,
Two international, double-blind, phase 3 Cardona-Muñoz EG,
An RCT showed efficacy of cyclophos-
RCTs compared belimumab 1 mg/kg and Celis A, et al. Therapy
phamide in mild and moderate pul- with intermittent
10 mg/kg plus standard therapy to pla- pulse cyclophos-
monary hypertension in patients with SLE
cebo plus standard therapy (58, 59). In the phamide for pul-
by reducing pulmonary artery systolic monary hyperten-
52-week study, reduction of ≥4 points on sion associated with
pressure and improving the New York
the SLE Response Index (SRI) was 51% and systemic lupus ery-
Heart Association functional class (53). thematosus. Lupus.
58% with the belimumab 1-mg/kg and 2004;13:105-12.
A retrospective study suggests that patients 10-mg/kg dose, respectively, vs. 44% with [PMID: 14995003]
54. Jais X, Launay D,
with SLE and mild to moderate pulmonary placebo (P<0.05). In the 76-week study, the Yaici A, et al. Im-
hypertension may respond to treatment with SRI-measured response at 52 weeks was munosuppressive
therapy in lupus-
cyclophosphamide and glucocorticoids, 42.8% and 46.5% with the belimumab and mixed connec-
while patients with more severe disease may 1-mg/kg and 10-mg/kg dose and 35.3% tive tissue disease-
associated pul-
require combination of vasodilators with im- with placebo; at 76 weeks, the response monary arterial
rates were 42.1% and 41.4% with the beli- hypertension: a ret-
munosuppressants (54). rospective analysis
mumab 1-mg/kg and 10-mg/kg dose, and of twenty-three cas-
A small study indicated that interstitial 33.8% with placebo (P<0.05 and P = NS, re- es. Arthritis Rheum.
2008;58:521-31.
lung disease treated with glucocorticoids spectively). Both trials excluded patients [PMID: 18240255]
for at least 1 week resulted in indolent pro- with severe lupus nephritis or severe CNS 55. Weinrib L, Sharma
OP, Quismorio FP Jr.
gression or stabilization over time (55). manifestations. Analysis of combined re- A long-term study of
sults from both trials showed more interstitial lung dis-
ease in systemic lu-
Larger clinical trials have not been improvement of musculoskeletal and mu- pus erythematosus.
done, and treatment decisions cocutaneous manifestations in patients Semin Arthritis
Rheum. 1990;20:48-
are based on clinical experience. treated with belimumab and improvement 56. [PMID: 2218553]

1 October 2013 Annals of Internal Medicine In the Clinic ITC4-11 © 2013 American College of Physicians

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 56. Pego-Reigosa JM,
Medeiros DA, Isen-
in immunologic parameters; in addition, What should clinicians do about
berg DA. Respiratory fewer patients had worsening hematologic immunizations in people with
manifestations of parameters (60).
systemic lupus ery- lupus?
thematosus: old and All patients with SLE should re-
new concepts. Best The SRI requires reduction in ceive influenza and pneumococcal
Pract Res Clin
Rheumatol. disease activity scores and no de- vaccinations. In addition, a recent
2009;23:469-80.
[PMID: 19591778] terioration from baseline in target study showed that the quadrivalent
57. Neumann R, Foster
CS. Corticosteroid-
organ manifestations (58). Fur- human papillomavirus vaccine is
sparing strategies in ther evidence is needed to assess well-tolerated and reasonably ef-
the treatment of
retinal vasculitis in the comparative efficacy of BlyS fective in patients with stable SLE
systemic lupus ery-
thematosus. Retina.
antagonism in severe lupus mani- and does not induce an increase in
1995;15:201-12. festations. lupus activity or flares (62). Pa-
[PMID: 7569347]
58. Furie R, Petri M, Za- tients receiving immunosuppres-
mani O, et al; BLISS- How should clinicians monitor sive therapy or daily prednisone
76 Study Group. A
phase III, random- patients who are being treated for >20 mg should not receive live at-
ized, placebo-con-
trolled study of beli-
lupus? tenuated vaccines, including her-
mumab, a Laboratory testing should include pes zoster (shingles), Flumist,
monoclonal anti-
body that inhibits B a complete blood count, basic measles-mumps-rubella, and
lymphocyte stimula-
tor, in patients with
metabolic panel, and urinalysis on smallpox. Tuberculin skin testing
systemic lupus ery- routine follow-up visits. These is recommended for SLE patients
thematosus. Arthritis
Rheum. tests allow the clinician to evalu- requiring prolonged treatment
2011;63:3918-30.
[PMID: 22127708]
ate for hematologic, renal, and with glucocorticoids or immuno-
59. Navarra SV, Guzmán other target-organ manifestations. suppressive therapy.
RM, Gallacher AE, et
al; BLISS-52 Study Many clinicians also routinely test
Group. Efficacy and for double-stranded DNA anti- How should clinicians modify
safety of belimumab
in patients with ac- bodies and complement C3 and treatment for pregnant patients?
tive systemic lupus
erythematosus: a C4 levels; however, this practice is Fertility is not significantly af-
randomised, place- controversial for clinically stable fected in SLE; however, flares
bo-controlled, phase
3 trial. Lancet. patients. Although a prospective occur at a higher rate during
2011;377:721-31.
RCT showed that 4-week pregnancy and the immediate
[PMID: 21296403]
60. van Vollenhoven RF,
treatment with prednisone of clin- postpartum period. The presence
Petri MA, Cervera R,
et al. Belimumab in ically stable but serologically ac- of anti-SSA antibodies may pre-
the treatment of sys-
tive patients averts a severe flare dict adverse pregnancy outcomes,
temic lupus erythe-
matosus: high dis-
(61), C3 and C4 and double- as may other factors, including
ease activity
antiphopsholipid antibodies, renal
predictors of re- stranded DNA antibodies are
sponse. Ann Rheum disease, thrombocytopenia, hyper-
Dis. 2012;71:1343-9. more useful in assessing SLE ac-
[PMID: 22337213] tension, and use of prednisone.
tivity in symptomatic patients or
61. Tseng CE, Buyon JP, Becoming pregnant during clini-
Kim M, et al. The ef- in assessing response to treatment.
fect of moderate- cal remission correlates with less
dose corticosteroids Other monitoring should be tai-
in preventing severe frequent and severe lupus exacer-
flares in patients lored to individual disease mani- bations. The initial presentation
with serologically ac- festations (Table 3). Consideration of SLE with hematologic or renal
tive, but clinically
stable, systemic lu- should be given to laboratory manifestations during pregnancy
pus erythematosus:
findings of a monitoring for immunosuppres- is not uncommon. Clinicians
prospective, ran-
domized, double-
sive medication toxicity and oph- should also consider pregnancy-
blind, placebo-con- thalmologic evaluation of patients related hematologic, vascular, and
trolled trial. Arthritis
Rheum. treated with hydroxychloroquine, renal abnormalities that mimic
2006;54:3623-32.
[PMID: 17075807]
particularly those older than SLE manifestations, including
62. Mok CC, Ho LY, Fong 40 years who have been treated for eclampsia and the HELLP syn-
LS, To CH. Immuno-
genicity and safety a long period. Clinicians should be drome (a group of symptoms that
of a quadrivalent hu-
man papillomavirus
alert to osteoporosis prevention occurs in pregnant women with
vaccine in patients and prescribe treatment when ap- hemolysis, elevated liver enzymes,
with systemic lupus
erythematosus: a propriate. Clinicians should also and low platelet counts). Anti-
case-control study.
Ann Rheum Dis.
consider periodic lipid testing and malarials can be used safely in
2013;72:659-64. order lipid-lowering agents, as pregnant SLE patients (63).
[PMID: 22589375]
needed. Active lupus manifestations in

© 2013 American College of Physicians ITC4-12 In the Clinic Annals of Internal Medicine 1 October 2013

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 pregnancy are usually treated with Table 3. Recommended Follow-up of Patients With SLE
hydroxychloroquine and pred- Issue How Frequency
nisone. It is advisable to continue
Disease activity History (rash, joint pain Quarterly
hydroxychloroquine in pregnancy constitutional symptoms);
because discontinuation is associ- physical examination;
ated with increased risk for flares CBC, urinalysis, CMP
and pregnancy is associated with Nephropathy CMP, urinalysis, urine protein– Quarterly, if inactive disease,
risk for increased disease activity. creatinine ratio or monthly, to assess response
Hydroxychloroquine may also to treatment
protect against cardiac manifesta- Hyperlipidemia Fasting lipid profile Yearly
tions of neonatal lupus.
Hydroxychloroquine toxicity History (visual disturbances); Yearly
For severe manifestions, IV gluco- ophthalmologic evaluation
corticoids and azathioprine may be
MMF, AZA toxicity CBC, CMP Every 8–12 wk or 4 wk after
considered because azathioprine change in dose
has not been identified as a human
teratogen (64). Mycophenolate Cervical dysplasia on Gynecologic examination; Yearly
immunosuppressants PAP smear, HPV test
mofetil, cyclophosphamide, and
methotrexate are contraindicated Osteonecrosis History, x-rays or MRI of With symptoms and history
due to potential teratogenicity. affected joint suggestive of avascular necrosis

When should patients with lupus Thrombosis History, examination venous With symptoms or signs
duplex studies, imaging for suggestive of thrombosis
be hospitalized? pulmonary embolism
Patients with serious complica-
tions should be hospitalized. Pulmonary hypertension Echocardiography Yearly, or as clinically indicated
Indications include severe throm- Osteoporosis DEXA Every 1–2 years, while on
bocytopenia, severe or rapidly pro- steroids
gressive renal disease, suspected
Planned pregnancy Antiphospholipid antibodies Before conception
lupus pneumonitis or pulmonary urinalysis, anti-SSA/SSB
hemorrhage, and severe cardiovas- antibodies, CBC, CMP, and
cular or CNS manifestations. A complement C3 and C4
major cause of death in SLE is in-
Patient education Every visit
fection, including from oppor-
tunistic pathogens. SLE patients
AZA = azathioprine; CBC = complete blood count; CMP = comprehensive metabolic panel;
with unexplained fever should be DEXA = dual x-ray absorptiometry; HPV= human papillomavirus; MMF = mycophenolate mofetil;
hospitalized for evaluation and MRI = magnetic resonance imaging; PAP = Papanicolaou.
initiation of treatment with antibi-
otics. Empirical coverage should
include Staphyloccocus aureus,
Pseudomonas species, Klebsiella and rapidly evaluated with appro-
species, Escherichia coli, and Acineto- priate imaging, cerebrovascular
bacter species. Chest pain in lupus fluid analysis, echocardiogram, and
patients could be due to coronary laboratory studies. 63. Costedoat-
Chalumeau N,
artery disease, serositis, pulmonary When should clinicians consider Amoura Z, Duhaut P,
et al. Safety of hy-
embolism, or esophageal disease. consulting a rheumatologist or droxychloroquine in
Lupus increases the risk for en- other specialist?
pregnant patients
with connective tis-
dothelial dysfunction, and long-term A rheumatologist should be in- sue diseases: a study
of one hundred thir-
treatment with steroids increases volved in the treatment of all lupus ty-three cases com-
traditional risk factors for coronary patients (66). Other specialists also
pared with a control
group. Arthritis
artery disease (65). Neurologic may be involved, according to or- Rheum.
2003;48:3207-11.
symptoms in lupus patients may gan-specific disease manifestations. [PMID: 14613284]
be due to neuropsychiatric lupus, 64. Natekar A, Pupco A,
Bozzo P, Koren G.
infection, the antiphospholipid What nondrug therapies should Safety of azathio-
prine use during
syndrome, or hypertension. All lu- clinicians recommend? pregnancy. Can Fam
pus patients with acute neurologic All lupus patients should be Physician.
2011;57:1401-2.
manifestations should be admitted counseled on low-cholesterol diet, [PMID: 22170192]

1 October 2013 Annals of Internal Medicine In the Clinic ITC4-13 © 2013 American College of Physicians

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 exercise, weight control, and smok- such as osteoporosis or the Sjogren
ing cessation. They should also be syndrome, is also recommended. All
advised about protection from ultra- patients should be counseled on the
violet rays to reduce flares from sun daily requirements for calcium and
exposure. Prevention or treatment of vitamin D to prevent osteoporosis.
65. Petri M, Lakatta C,
complications due to conditions Routine dental evaluation is also
Magder L, et al. Ef- commonly associated with lupus, recommended.
fect of prednisone
and hydroxychloro-
quine on coronary
artery disease risk
factors in systemic
lupus erythemato-
Treatment... Hydroxychloroquine prevents disease flares and is considered the
sus: a longitudinal cornerstone of SLE treatment. Glucocorticoids are first-line agents for most SLE
data analysis. Am J manifestations, with dosage and treatment duration based on clinical experience
Med. 1994;96:254-9.
[PMID: 8154514] and consensus. Immunosuppressive treatment in lupus nephritis is based on
66. Gabriel S, Tugwell P, histopathologic classification and guided by ACR recommendations. Treatment of
O’Brien B, et al. Re-
port of the OMER-
other lupus manifestations is based on sparse evidence from clinical trials and
ACT task force on clinical experience and often requires immunosuppressive therapy and a multidis-
economic evalua- ciplinary approach.
tion. Outcome
Measures in
Rheumatology. J
Rheumatol.
1999;26:203-6.
CLINICAL BOTTOM LINE
[PMID: 9918264]

In the Clinic PIER Module

In the Clinic
http://smartmedicine.acponline.org/content.aspx?gbosId=153

Tool Kit
Smart Medicine module on systemic lupus erythematosus (SLE)
from the American College of Physicians.

Patient Information
www.nlm.nih.gov/medlineplus/lupus.html
www.nlm.nih.gov/medlineplus/tutorials/lupus/htm/index.htm
www.nlm.nih.gov/medlineplus/spanish/tutorials/lupusspanish/
Systemic Lupus htm/index.htm
Erythematosus Resources related to lupus from the National Institutes of Health’s
MedlinePLUS, including an interactive tutorial in English and
Spanish.
www.niams.nih.gov/Health_Info/Lupus/lupus_ff.asp
www.niams.nih.gov/Portal_En_Espanol/Informacion_de_Salud/Lupus/
default.asp
Answers to common questions about lupus from the National Institute
of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), in
English and Spanish.
www.nlm.nih.gov/medlineplus/ency/article/000481.htm
Information about lupus nephritis, a complication of SLE from
NIAMS.

Clinical Guidelines
www.rheumatology.org/Practice/Clinical/Guidelines/Glucocorticoid
-Induced_Osteoporosis_(Members__Only)/
Recommendations for the prevention and treatment of glucocorticoid-
induced osteoporosis from the American College of Rheumatology
(ACR) in 2010.
Diagnostic Tests and Criteria
pier.acponline.org/physicians/diseases/d208/tables/d208
-tlab.html
List of laboratory and other studies for SLE from PIER.
www.rheumatology.org/practice/clinical/position/ana_position
_stmt.pdf
Position statement on the methodology of testing for antinuclear
antibodies from the ACR in 2011.

© 2013 American College of Physicians ITC4-14 In the Clinic Annals of Internal Medicine 1 October 2013

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 THINGS YOU SHOULD In the Clinic
Annals of Internal Medicine
KNOW ABOUT LUPUS

What is lupus?
• A chronic disease that occurs when the body’s de-
fense system (the immune system) wrongly attacks
its own tissues.
• The result can be pain and swelling (inflammation)
that affects the skin, joints, kidneys, and other
organs.
• Symptoms range from mild to serious and fluctuate
between times when the disease is active (a flare)
and times when it is quiet (remission).
• The cause is unclear.
• Lupus usually starts when people are in their 20s
and 30s and is 10 times more common in women
than in men.

What are the signs and symptoms?

• Fatigue.
• Rashes (particularly a butterfly-shaped rash over the
cheeks or a red rash with raised round or oval
patches).
• Painful and swollen joints.
• Sores in the mouth or nose.
• Chest pain when breathing deeply, from swelling of
the tissue lining the lungs (pleurisy or pleuritis) or
the heart (pericarditis).
• Mental health problems, seizures, or strokes.
• Fever.
• Kidney problems, liver disease, clogged arteries
(atherosclerosis).

How is it diagnosed?

• Your doctor will examine you carefully and ask you
about your symptoms.
• Your doctor may order blood tests that can help
confirm whether you have the disease.
How is it treated?
• Nonsteroidal anti-inflammatory drugs to decrease
swelling, pain, and fever.
Patient Information
• Antimalarial drugs (such as hydroxychloroquine) to
reduce fatigue, rashes, joint pain, and mouth sores.
• Corticosteroids or biologics, a new type of drug for
rheumatic diseases, to reduce inflammation.
• Treatment is based on the symptoms and the severity
of the disease.

For More Information

www.niams.nih.gov/Health_Info/Lupus/default.asp
Booklet on SLE to help people understand the disease and how
to cope with it, from the NIAMS.

www.rheumatology.org/Practice/Clinical/Patients/Diseases_And
_Conditions/Systemic_Lupus_Erythematosus_(Lupus)/
www.rheumatology.org/Practice/Clinical/Patients/Diseases_And
_Conditions/Lupus_Eritematoso_Sistemico_(Lupus)_(Español)/
Information about SLE from the ACR, in English and Spanish.

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 CME Questions
1. A 25-year-old woman is evaluated for a
1-year history of scaly plaques on her
face and scalp. Results of a skin biopsy
1 week ago are consistent with chronic
cutaneous lupus. She has ongoing mild
fatigue, a 10-day history of lower back
pain, and occasional migraine headaches
for which she takes sumatriptan as
needed. She also has a history of partial-
onset seizures that began at age 13 years
for which she currently takes phenytoin.
On physical examination, temperature is
37.0°C (98.6°F), blood pressure is
125/73 mm Hg, pulse rate is 72/min, and
respiration rate is 16/min. Cutaneous
examination reveals scattered circular
plaques on the cheeks, nose, scalp, and
ear canals. Within the plaques, there is
follicular plugging and atrophic scarring.
She also has patches of alopecia where
the rash is present on the scalp.
Cardiopulmonary examination is normal.
There is no lymphadenopathy or oral
ulcers. Abdominal examination is
unremarkable. Musculoskeletal
examination reveals no synovitis, and
neurologic examination is normal.
Laboratory studies reveal the following:
hemoglobin, 14 g/dL (140 g/L); leukocyte
count, 6300/µL (6.3 × 109/L); erythrocyte
sedimentation rate, 16 mm/h; serum
creatinine, 0.8 mg/dL (61.0 µmol/L);
serum complement (C3 and C4), normal;
antinuclear antibodies, titer of 1:160;
anti–double-stranded DNA antibodies,
negative; anti-Ro/SSA antibodies,
negative; anti-La/SSB antibodies,
negative; anti-Smith antibodies,
negative; antiribonucleoprotein
antibodies, negative; antihistone
antibodies, negative; urinalysis, normal.
Which of the following is the most likely
diagnosis?
A. Discoid lupus
B. Drug-induced lupus
C. Mixed connective tissue disease
D. Systemic lupus erythematosus
Questions are largely from the ACP’s Medical Knowledge Self-Assessment Program (MKSAP, accessed at
http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/
to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.
© 2013 American College of Physicians
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2. A 28-year-old woman with systemic
lupus erythematosus (SLE) is evaluated in
the office after obtaining positive results
on a home pregnancy test. She has a
1-month history of nausea but is
otherwise asymptomatic. Her last
menstrual period was 2 months ago. This
is her first pregnancy. Her SLE is well-
controlled with hydroxychloroquine, and
her last flare was 10 months ago.
On physical examination, temperature is
36.2°C (97.2°F), blood pressure is
110/72 mm Hg, pulse rate is 76/min,
and respiration rate is 16/min. Physical
examination is normal. A repeated
pregnancy test is positive.
Laboratory studies reveal the following:
hemoglobin, 12.1 g/dL (121 g/L);
leukocyte count, 5400/µL (5.4 × 109/L);
platelet count, 342 000/µL (342 × 109/L);
serum creatinine, 0.7 mg/dL (53.4 µmol/L);
serum complement (C3 and C4), normal;
antinuclear antibodies, titer of 1:2560;
anti-Ro/SSA antibodies, positive;
anti–double-stranded DNA antibodies ,
negative; anti-Smith antibodies,
positive;urinalysis, normal.
She seeks advice on how to manage her
SLE during her pregnancy.
Which of the following is the most
appropriate management of this patient?
A. Discontinue hydroxychloroquine
B. Recommend termination of pregnancy
C. Start prednisone
D. No change in management
3. A 43-year-old woman with SLE is
admitted to the hospital for a 1-week
history of worsening headache and a
2-day history of confusion, personality
change, and emotional lability. She was
diagnosed with lupus 1 year ago, and her
condition has been well-controlled with
prednisone, hydroxychloroquine, and
ibuprofen. Four months ago, prednisone
was discontinued.
Two months ago, she developed fatigue,
intermittent low-grade fevers, and
ITC4-16 In the Clinic
occasional headache. Two weeks ago, she
was evaluated in the office for a
1-month history of purpuric lesions on
her legs, palms, and soles. Biopsy
specimen of a lesion showed
leukocytoclastic vasculitis. At that time,
prednisone, 40 mg/d, was initiated, and
the purpuric lesions began to fade.
On physical examination today,
temperature is 37.9°C (100.2°F), blood
pressure is 150/80 mm Hg, pulse rate is
102/min, and respiration rate is 20/min.
The purpuric lesions persist. She is
confused and oriented to name only,
intermittently laughs and cries, and has
paranoid ideation. She does not have
photophobia or nuchal rigidity, and the
neurologic examination is nonfocal.
Laboratory studies show the following:
hemoglobin, 11.1 g/dL (111 g/L); leuko-
cyte count, 3500/µL (3.5 × 109/L); plate-
let count, 200 000/µL (200 × 109/L);
erythrocyte sedimentation rate, 83 mm/h;
serum complement (C3 and C4), de-
creased; ANA, titer of 1:2560. Cerebro-
spinal fluid findings are as follows:
leukocyte count, 55/µL (100% lympho-
cytes); erythrocyte count, 1/µL; protein,
72 mg/dL (720 mg/L); gram stain,
negative; venereal disease, negative.
Culture results are pending. T2-weighted
magnetic resonance imaging of the brain
reveals scattered punctate areas of
increased signal in the periventricular
and subcortical white matter.
Which of the following is the most
appropriate next step in this patient’s
treatment?
A. Begin ampicillin and gentamicin
B. Begin methylprednisolone and
cyclophosphamide
C. Discontinue ibuprofen
D. Schedule plasmapheresis
Annals of Internal Medicine 1 October 2013