In the Clinic Systemic Lupus Erythematosus In...

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Systemic LupusErythematosusScreening 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 WriterMarianthi Kiriakidou MD

Section EditorsDeborah Cotton, MD, MPHDarren Taichman, MD, PhDSankey Williams, MD

The content of In the Clinic is drawn from the clinical information and educationresources of the American College of Physicians (ACP), including PIER (Physicians’Information and Education Resource) and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinicfrom these primary sources in collaboration with the ACP’s Medical Education andPublishing divisions and with the assistance of science writers and physician writ-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 canconsult 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 clinicaljudgment.

© 2013 American College of Physicians

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Which patients are at elevatedrisk for lupus?Evidence to determine whetherpeople may be at risk for lupusbecause of specific genes is insuf-ficient. Early genetic studies,driven by the observation of fa-milial aggregation and high con-cordance in monozygotic twins,have implicated genes for HLAand early complement compo-nents (3). A few rare, single-generisk factors have been linked toSLE. For example, C1, C2, or C4genetic deficiencies can cause lu-pus but account for just 1–2% ofcases (3). Recent genome-wideassociation studies have linkedmore than 30 gene polymor-phisms to lupus (4). However, thefunctional significance of thesevariants and their potential im-plication to SLE pathogenesis remain largely unknown. In addi-tion, sex chromosome genes, and possibly sex hormones andenvironmental influences, may contribute to immune system

dysfunction in genetically predis-posed individuals.

Should clinicians screenasymptomatic patients for lupus ifthey are at increased risk?Most experts do not recommendscreening asymptomatic personsfor lupus, even those with a fami-ly history. Nevertheless, the im-munologic test for antinuclear antibody (ANA) is often used forSLE screening even though itproduces many false-positive re-sults. ANA is detected in 3–5% ofhealthy individuals or patientswith other autoimmune or infec-tious diseases. Furthermore, sero-logic evidence of ANAs, whichindicates immune system activa-tion, may precede the clinicalmanifestations required for diag-nosis by 3 to 9 years (5). No evi-dence suggests that treating tomodulate the immune systemduring this clinically “silent” peri-od can stop or delay lupus devel-opment.

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

1. Demas KL, Costen-bader KH. Disparitiesin lupus care andoutcomes. Curr OpinRheumatol.2009;21:102-9.[PMID: 19339919]

2. Bernatsky S, Boivin JF,Joseph L, et al. Mor-tality in systemic lu-pus erythematosus.Arthritis Rheum.2006;54:2550-7.[PMID: 16868977]

3. Sestak AL, FürnrohrBG, Harley JB, et al.The genetics of sys-temic lupus erythe-matosus and implica-tions for targetedtherapy. Ann RheumDis. 2011;70 Suppl1:i37-43.[PMID: 21339217]

4. Deng Y, Tsao BP. Ge-netic susceptibility tosystemic lupus ery-thematosus in thegenomic era. Nat RevRheumatol.2010;6:683-92.[PMID: 21060334]

5. Arbuckle MR, McClainMT, Rubertone MV, etal. Development ofautoantibodies be-fore the clinical onsetof systemic lupus ery-thematosus. N Engl JMed. 2003;349:1526-33. [PMID: 14561795]

6. Seibold JR, WechslerLR, Cammarata RJ. LEcells in intermittenthydrarthrosis [Letter].Arthritis Rheum.1980;23:958-9.[PMID: 6157396]

7. Ball EM, Bell AL. Lupusarthritis—-do wehave a clinically use-ful classification?Rheumatology (Ox-ford). 2012;51:771-9.[PMID: 22179731]

8. Patel P, Werth V. Cuta-neous lupus erythe-matosus: a review.Dermatol Clin.2002;20:373-85, v.[PMID: 12170873]

9. Alarcón GS, FriedmanAW, Straaton KV, et al.Systemic lupus ery-thematosus in threeethnic groups: III. Acomparison of char-acteristics early in thenatural history of theLUMINA cohort. LU-pus in MInority popu-lations: NAture vs.Nurture. Lupus.1999;8:197-209.[PMID: 10342712]

10. Chang AY, Werth VP.Treatment of cuta-neous lupus. CurrRheumatol Rep.2011;13:300-7.[PMID: 21503694]

Systemic lupus erythematosus (SLE, lupus) is a condition in which theimmune 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 tissue deposition of immune complexes, and complement and cytokine acti-vation contribute to clinical manifestations that range from mild fatigue andjoint pain to severe, life-threatening organ damage.

Because the symptoms of SLE vary widely and the condition often goes undiagnosed, it is unclear how many people in the United States have thedisease. It is diagnosed 9 times more often in women than in men, whichimplies pathogenic mechanisms more prevalent in women. These mecha-nisms, which probably involve effects of sex chromosomes, specific genes,and hormones, have not been completely elucidated. SLE is more commonand more severe in African American women, Hispanic women, and thoseof other ethnic minorities (1).

Although there is no cure for SLE, it can be effectively managed with med-ications; however, mortality is higher in patients with SLE than in the gen-eral population. The overall standardized mortality ratio (SMR) (ratio ofdeaths observed to deaths expected for an age group) for SLE is 2.4. Higherrisk for death is associated with female sex, younger age, shorter SLE dura-tion, and African American race (2).

Screening


© 2013 American College of PhysiciansITC4-3In the ClinicAnnals of Internal Medicine1 October 2013

What symptoms or physicalexamination findings shouldprompt clinicians to consider adiagnosis of lupus?The initial presentation of lupus of-ten mimics a viral syndrome. Suchconstitutional symptoms as weightloss, fatigue, and low-grade fever arecommon and may be accompaniedby arthralgias or arthritis. Arthritisin lupus is characterized by pro-longed morning stiffness and mildto moderate joint swelling. It isnonerosive, may be symmetric orasymmetric, and may affect large orsmall joints. Large effusions are notas common in lupus as in rheuma-toid arthritis, and the synovial fluidis not as inflammatory (6). Jointdeformities are not frequent in lu-pus. Jaccoud arthropathy, whichmay include reducible ulnar devia-tion, swan neck deformities, or z-shaped thumb, is present in2.8–4.3% of patients (7). Whenconstitutional symptoms witharthralgias or arthritis are not ac-companied by other characteristicmanifestations of lupus, such asphotosensitive skin rash on theface, neck, or extremities, it is ap-propriate to conduct a clinical andlaboratory evaluation for infectionbefore trying to establish a diagno-sis of SLE.

Cutaneous manifestations are com-mon and may occur in up to 70%of patients (8). They are catego-rized as acute, subacute, or chronic.Acute cutaneous lupus consists ofindurated or flat erythematous lesions on the malar eminences,scalp, arms, hands, neck, and chest.

The malar rash may be confusedwith rosacea, drug eruption, orpolymorphous light eruption, butskin biopsy is rarely necessary whenother clinical manifestations andserologic evidence consistent withSLE are present. Subacute cuta-neous lupus consists of annular lesions that may coalesce into apolycyclic (overlapping ring-shaped)rash or papulosquamous lesions that do not scar and are distributedwhere light exposure is most fre-quent. It is often associated withanti-SSA antibodies. Chronic cuta-neous lupus includes discoid lupusand other rare subsets, such as lupuspanniculitis, hypertrophic lupus ery-thematosus (characterized by verru-cous lesions), tumid lupus or lupustumidus (smooth, shiny, red-violetplaques usually on the head andneck), and chilblain lupus (purplish-blue lesions on the fingers, toes, orears). Discoid lupus is the mostcommon form of the chronic cuta-neous disease and is characterizedby scarring indurated plaques thatresolve with significant depigmenta-tion. Although acute cutaneous lu-pus is nearly always associated withsystemic lupus, discoid lupus is in-frequently (3–5%) associated withsystemic disease (9).

What other clinical manifestationsshould clinicians look for inpotential cases of lupus?Systemic lupus may present inmany other ways. Although fever,rash, and arthritis are the classicinitial symptoms, abrupt onset withtarget-organ involvement is alsoquite common, particularly in

11. Vilá LM, Alarcón GS,McGwin G Jr, et al;Lumina StudyGroup. Systemic lu-pus erythematosusin a multiethnic UScohort, XXXVII: asso-ciation of lymphope-nia with clinicalmanifestations, sero-logic abnormalities,disease activity, anddamage accrual.Arthritis Rheum.2006;55:799-806.[PMID: 17013840]

12. Durán S, Apte M,Alarcón GS, et al; Lu-mina Study Group.Features associatedwith, and the impactof, hemolytic anemiain patients with sys-temic lupus erythe-matosus: LX, resultsfrom a multiethniccohort. ArthritisRheum.2008;59:1332-40.[PMID: 18759263]

13. Bomback AS, AppelGB. Updates on thetreatment of lupusnephritis. J Am SocNephrol.2010;21:2028-35.[PMID: 21051743]

14. Cervera R, Khamash-ta MA, Font J, et al;European WorkingParty on SystemicLupus Erythemato-sus. Morbidity andmortality in systemiclupus erythemato-sus during a 10-yearperiod: a compari-son of early and latemanifestations in acohort of 1,000 pa-tients. Medicine (Bal-timore). 2003;82:299-308.[PMID: 14530779]

15. Mok CC, Kwok RC,Yip PS. Effect of renaldisease on the stan-dardized mortalityratio and life ex-pectancy of patientswith systemic lupuserythematosus.Arthritis Rheum.2013;65:2154-60.[PMID: 23754671]

16. Kamen DL, StrangeC. Pulmonary mani-festations of sys-temic lupus erythe-matosus. Clin ChestMed. 2010;31:479-88. [PMID: 20692540]

17. Peponis V, KyttarisVC, Tyradellis C, et al.Ocular manifesta-tions of systemic lu-pus erythematosus:a clinical review. Lu-pus. 2006;15:3-12.[PMID: 16482739]

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

CLINICAL BOTTOM LINE

Diagnosis


18. Hochberg MC. Up-dating the AmericanCollege of Rheuma-tology revised crite-ria for the classifica-tion of systemiclupus erythemato-sus [Letter]. ArthritisRheum.1997;40:1725.[PMID: 9324032]

19. Petri M, Orbai AM,Alarcón GS, et al.Derivation and vali-dation of the Sys-temic Lupus Interna-tional CollaboratingClinics classificationcriteria for systemiclupus erythemato-sus. Arthritis Rheum.2012;64:2677-86.[PMID: 22553077]

20. Sun S, Rao NL, Ven-able J, Thurmond R,Karlsson L. TLR7/9antagonists as thera-peutics for immune-mediated inflamma-tory disorders.Inflamm AllergyDrug Targets.2007;6:223-35.[PMID: 18220957]

21. Ben-Zvi I, Kivity S,Langevitz P, Shoen-feld Y. Hydroxy-chloroquine: frommalaria to autoim-munity. Clin Rev Al-lergy Immunol.2012;42:145-53.[PMID: 21221847]

22. Farrell DF. Retinaltoxicity to antimalar-ial drugs: chloro-quine and hydroxy-chloroquine: aneurophysiologicstudy. Clin Ophthal-mol. 2012;6:377-83.[PMID: 22457587]

23. Mackworth-YoungCG, David J, MorganSH, et al. A doubleblind, placebo con-trolled trial of intra-venous methylpred-nisolone in systemiclupus erythemato-sus. Ann Rheum Dis.1988;47:496-502.[PMID: 3289511]

24. Albert DA, HadlerNM, Ropes MW.Does corticosteroidtherapy affect thesurvival of patientswith systemic lupuserythematosus?Arthritis Rheum.1979;22:945-53.[PMID: 475873]

25. Edwards JC, SnaithML, Isenberg DA. Adouble blind con-trolled trial ofmethylprednisoloneinfusions in systemiclupus erythemato-sus using individu-alised outcome as-sessment. AnnRheum Dis.1987;46:773-6.[PMID: 3318723]


Hispanics (61%) and AfricanAmericans (45%), as comparedwith white patients (41%) (10).SLE should be considered whenpatients, particularly women of re-productive age, present with hema-tologic, renal, respiratory, or centralnervous system (CNS) manifesta-tions, especially hematologic find-ings, such as thrombocytopenia,leukopenia, lymphopenia, or ane-mia; renal findings, such as hema-turia, proteinuria, cellular casts, orelevated serum creatinine; respira-tory symptoms, such as cough, dys-pnea, hemoptysis, or pleuritic pain;or CNS signs, such as headache,photophobia, or focal neurologicdeficits.

Hematologic manifestationsCytopenias are common in patientswith lupus, and moderate-to-severelymphopenia is associated withhigh disease activity and organdamage (11). Hemolytic anemia isuncommon and usually associatedwith disease onset, thrombocy-topenia, and African Americanethnicity (12).

Renal manifestationsRenal involvement is a commontarget-organ manifestation; it hasa poor prognosis due to the highrisk for organ failure. Up to 50% of SLE patients have some evidence of renal disease at presen-tation (13). SLE nephritis is asso-ciated with a worse prognosis for10-year survival than the nonrenaldisease (14). Compared with thegeneral population, life expectancyis reduced by 12.4, 15.1, and 23.7years in lupus patients, those withrenal disease, and those with renaldamage, respectively (15).

Respiratory involvementInvolvement of the respiratory sys-tem may be primary or secondary.Presenting symptoms and the re-sponse to treatment vary, depend-ing on the affected anatomical site.Pleuritis is the most common respiratory SLE manifestation,

affecting 30–50% of patients (16).Lupus pleuritis should be diag-nosed only after an analysis ofpleural fluid and an evaluation forother causes of pleural effusion,such as infection, pulmonary em-bolism, liver disease, heart disease,and cancer. Bronchoscopy for bac-terial, mycobacterial, fungal, and viralcultures may be indicated. Vascularinvolvement may cause diffusealveolar hemorrhage, pulmonaryhypertension, or thromboembolicdisease. Parenchymal damage is lesscommon and may be the result ofinterstitial lung disease, acute pneu-monitis, or bronchiolitis obliteranswith organizing pneumonia. Acutelupus pneumonitis is rare and car-ries a high mortality risk. Infectionand pulmonary embolism must al-ways be excluded in patients withsuspected lupus pneumonitis.

Neuropsychiatric manifestationsNeuropsychiatric SLE manifesta-tions may be caused by vasculopathy,autoantibodies, and inflammatorymediators and include headache,aseptic meningitis, vasculitis, move-ment disorder, seizure disorder, cognitive dysfunction, psychosis, demyelinating disease, myelopathy,autonomic disorder, and peripheralneuropathy.

Ocular manifestationsOcular manifestations include kera-toconjuctivitis sicca (with or withoutthe Sjogren syndrome), keratitis,episcleritis, scleritis, uveitis, retinalvasculitis, occlusion of the retinalartery or vein, retinopathy, and nu-merous other less common mani-festations (17).

Gastrointestinal manifestationsGastrointestinal symptoms mayinclude anorexia, nausea, vomit-ing, abdominal pain, and diarrhea.Other causes of abdominal pain inlupus are mesenteric vasculitis andhepatobiliary disease. Rare gas-trointestinal complications includeintestinal pseudo-obstruction,protein-losing enteropathy, and



pancreatitis. Immunocompromisedlupus patients are also prone toenteritis from cytomegalovirus orsalmonella infection.

Lupus is a multiorgan disease thatcan mimic infectious diseases, can-cer, and other autoimmune condi-tions. Table 1 lists the AmericanCollege of Rheumatology (ACR)classification criteria for SLE (18).These criteria facilitate a systemat-ic approach to diagnosis by focus-ing on the most common SLEmanifestations. Four of the 11 cri-teria are required for classificationof systemic lupus. Although in-tended to assist in classification,the ACR criteria offer a highlysensitive and specific tool for

diagnosing SLE, based on objectivedisease manifestations. However,patients with mild disease may bemissed. In 2012 the Systemic Lu-pus International CollaboratingClinics revised the ACR classifica-tion criteria, increasing the sensitiv-ity but not the specificity ofdetecting SLE compared with the1997 ACR criteria (19).

What laboratory tests shouldclinicians use to diagnose lupus?Clinicians should test for ANA,and if the result is positive, follow-up testing for antigen-specificANAs, such as those targeting double-stranded DNA (dsDNA) orribonucleoprotein complexes(Ro/SSA, La/SSB, Smith, and

26. Badsha H, Kong KO,Lian TY, et al. Low-dose pulse methyl-prednisolone for sys-temic lupuserythematosus flaresis efficacious andhas a decreased riskof infectious compli-cations. Lupus.2002;11:508-13.[PMID: 12220105]

27. Buttgereit F, da SilvaJA, Boers M, et al.Standardisednomenclature forglucocorticoiddosages and gluco-corticoid treatmentregimens: currentquestions and tenta-tive answers inrheumatology. AnnRheum Dis.2002;61:718-22.[PMID: 12117678]

28. Da Silva JA. Safety ofglucocorticoids -clinical trials. ClinExp Rheumatol.2011;29:S99-103.[PMID: 22018193]

29. Carneiro JR, Sato EI.Double blind, ran-domized, placebocontrolled clinicaltrial of methotrexatein systemic lupuserythematosus. JRheumatol.1999;26:1275-9.[PMID: 10381042]

30. Islam MN, HossainM, Haq SA, et al. Effi-cacy and safety ofmethotrexate in ar-ticular and cuta-neous manifesta-tions of systemiclupus erythemato-sus. Int J Rheum Dis.2012;15:62-8.[PMID: 22324948]

31. Fortin PR, Abra-hamowicz M, Fer-land D, et al; Canadi-an Network ForImproved Outcomesin Systemic Lupus.Steroid-sparing ef-fects of methotrex-ate in systemic lupuserythematosus: adouble-blind, ran-domized, placebo-controlled trial.Arthritis Rheum.2008;59:1796-804.[PMID: 19035431]

32. Gourley MF, AustinHA 3rd, Scott D, et al.Methylprednisoloneand cyclophos-phamide, alone or incombination, in pa-tients with lupusnephritis. A random-ized, controlled trial.Ann Intern Med.1996;125:549-57.[PMID: 8815753]

Table 1. American College of Rheumatology Classification Criteria for SLE*Criterion Definition

Malar rash Flat or raised erythema over the malar eminences, sparing the nasolabial folds

Discoid rash Erythematous raised patches or atrophic scarring (older lesions)

Photosensitivity Skin rash as a result of unusual reaction to sunlight

Oral ulcers Usually painless oral or nasopharyngeal ulcerations, observed by physician

Arthritis Nonerosive arthritis, involving 2 or more peripheral joints characterized by tenderness and swelling

Serositis Pleuritis: Convincing history of pleuritic pain or rubbing heard by physician, or evidence of pleural effusionPericarditis: Documented by electrocardiogram, or rub or evidence of pericardial effusion

Renal disorder Persistent proteinuria >0.5 g/d or >3 on dipstickCellular casts red cell, hemoglobin, granular, tubular, or mixed

Neurologic disorder Seizures (in the absence of offending drugs or metabolic derangement)Psychosis (in the absence of offending drugs or metabolic derangement)

Hematologic disorder Hemolytic anemia: with reticulocytosisLeukopenia: <4000/mm on 2 or more occasionsLymphopenia: <1500/mm on 2 or more occasionsThrombocytopenia: <100 000/mm in the absence of offending drugs

Immunologic disorder Anti-DsDNAAnti-Smith antibodiesAntiphospholipid antibodies based on an abnormal serum level of IgG or IgM anticardiolipin antibodies, positive test result for lupus anticoagulant using a standard method, or false-positive serologic test result for syphilis known to be positive for at least 6 mo and confirmed as false-positive by Treponema pallidum immobilization or fluorescent treponemal antibody absorption tests

Antinuclear antibody Detected by immunofluoresence (or equivalent assay) in the absence of drugs known to be associated with drug-induced SLE

*From reference 18.


33. Illei GG, Austin HA,Crane M, et al. Com-bination therapywith pulse cy-clophosphamideplus pulse methyl-prednisolone im-proves long-term re-nal outcomewithout adding toxi-city in patients withlupus nephritis. AnnIntern Med.2001;135:248-57.[PMID: 11511139]

34. Hochstadt A, Roz-man Z, Zandman-Goddard G. [My-cophenolate mofetilas a novel treatmentfor lupus nephritis].Harefuah.2011;150:542-7, 550.[PMID: 21800496]

35. Anderka MT, Lin AE,Abuelo DN, et al. Re-viewing the evi-dence for mycophe-nolate mofetil as anew teratogen: casereport and review ofthe literature. Am JMed Genet A.2009;149A:1241-8.[PMID: 19441125]

36. Kamanamool N,McEvoy M, Attia J, etal. Efficacy and ad-verse events of my-cophenolate mofetilversus cyclophos-phamide for induc-tion therapy of lupusnephritis: systematicreview and meta-analysis. Medicine(Baltimore).2010;89:227-35.[PMID: 20616662]

37. Touma Z, GladmanDD, Urowitz MB, etal. Mycophenolatemofetil for inductiontreatment of lupusnephritis: a system-atic review andmetaanalysis. JRheumatol.2011;38:69-78.[PMID: 20952473]


RNP, which are collectively referredto as extractable nuclear antigens)should be done. The specificity ofanti ds-DNA antibodies for lupus is>60%. Anti-Smith antibodies are>90% specific for lupus; however,they are detected in only about 30%of lupus patients. The initial labora-tory evaluation to assess disease ac-tivity and target-organ involvementis described in the Box (Basic Inves-tigations for SLE).

What other diagnoses shouldclinicians consider?The chronic fatigue syndrome and fi-bromyalgia may present with diffusemusculoskeletal symptoms mimick-ing lupus, or may be secondary toSLE. SLE can be excluded in the ab-sence of inflammatory pain and neg-ative results on serologic evaluation.Rheumatoid arthritis is characterizedby symmetric, intensely inflammatory,erosive arthritis (when advanced) andpositive results on rheumatoid factoror anti-CCP antibody testing.

Such drugs as procainamide, hy-dralazine, minocycline, isoniazide,and tumor necrosis factor inhibitorscan cause drug-induced lupus, a clin-ical syndrome resembling SLE char-acterized by fever, serositis, arthritis,and rash. Antihistone antibodies aredetected in approximately 75% of pa-tients; however, they can also be seenin SLE and are not pathognomonic.Anti-dsDNA, or antibodies to

extractable nuclear antigens, are rarein drug-induced lupus, and symp-toms usually abate within days orweeks after drug discontinuation.

Small- or medium-vessel vasculitides,thrombotic thrombocytopenic pur-pura, and viral arthritis, as seen inparvovirus infection and HIV/AIDS,can also mimic SLE. Differential di-agnosis relies on laboratory studies,detection of viral serologies, and tis-sue histopathology. Hematopoieticcancer and malignant lymphoprolif-erative syndromes may present withpositive ANA, anemia, low-gradefever, pleural effusions, and lym-phadenopathy and can be misdiag-nosed as lupus.

When should clinicians considerconsulting with a rheumatologistor other specialist for diagnosingpatients with possible lupus?Clinicians should consult arheumatologist in all patients whenclinical manifestations and serolog-ic studies suggest SLE. Evidence ofrenal, pulmonary, CNS, ocular, orgastrointestinal disease necessitatesa coordinated, multidisciplinary ap-proach with the help of appropriatespecialists. The goal of care is atimely, accurate diagnosis; effectivetreatment of acute disease; appro-priate monitoring and dose adjust-ment; and early introduction of asteroid-sparing regimen.

Treatmentglucocorticoids, antimalarial agents,and nonsteroidal anti-inflammatorydrugs (NSAIDs) (Table 2). Hydroxy-chloroquine prevents disease flares

What medications are used totreat lupus?Clinicians use a broad range of med-ications to treat lupus, including

Diagnosis... Lupus is a multisystem disease that often presents as a diagnostic chal-lenge because it can include cutaneous, renal, respiratory, cardiovascular, CNS, andgastrointestinal manifestations that characterize numerous other conditions. The ACRclassification criteria can be used to guide the diagnosis of systemic lupus.


Basic Investigations for SLEComplete blood countDirect Coombs test (indicated if

patients present with hemolyticanemia and reticulocytosis)

Comprehensive metabolic panelErythrocyte sedimentation rateC-reactive proteinUrinalysisSerologic testing (ANA and if

positive, anti-DsDNA, anti-SSA/SSB, anti-Smith/RNP anti-phospholipid antibodies); anegative ANA test is inconsistentwith the diagnosis of SLE

Complement C3 and C4Creatine phosphokinase (indicated

in patients presenting withmuscle weakness)


38. Hahn BH, McMahonMA, Wilkinson A, etal; American Collegeof Rheumatology.American College ofRheumatologyguidelines forscreening, treat-ment, and manage-ment of lupusnephritis. ArthritisCare Res (Hoboken).2012;64:797-808.[PMID: 22556106]


and is considered the cornerstone ofSLE treatment. Glucocorticoids arefirst-line agents for most SLE mani-festations, with dosage and treatmentduration based on clinical experienceand consensus. Immunosuppressivetreatment in lupus nephritis is basedon histopathologic classifications.Treatment of other lupus manifes-tations is based on sparse evidencefrom clinical trials and clinical experience and often requires

immunosuppressive therapy and amultidisciplinary approach.

How should clinicians initiatetherapy in a stable patient who isnot having a flare?Hydroxychloroquine and other an-timalarial agents have been used totreat inflammatory arthritides forat least 50 years (20). In additionto preventing lupus relapses andreducing the risk for congenital

Table 2. Drug Treatment for SLEAgent 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 pressiondehydrogenase 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, hepatotoxicityproliferation

Methotrexate Inhibits DNA synthesis and increases 5–25 mg/wk (orally or sub- Gastrointestinal intolerance, hepatotoxicityrelease 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, bladderB-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, myelosuppressionexpression 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


39. Contreras G, Pardo V,Leclercq B, et al. Se-quential therapiesfor proliferative lu-pus nephritis. N EnglJ Med. 2004;350:971-80. [PMID: 14999109]

40. Dooley MA, Jayne D,Ginzler EM, et al;ALMS Group. My-cophenolate versusazathioprine asmaintenance thera-py for lupus nephri-tis. N Engl J Med.2011;365:1886-95.[PMID: 22087680]

41. Houssiau FA, D’CruzD, Sangle S, et al;MAINTAIN NephritisTrial Group. Azathio-prine versus my-cophenolate mofetilfor long-term im-munosuppression inlupus nephritis: re-sults from the MAIN-TAIN Nephritis Trial.Ann Rheum Dis.2010;69:2083-9.[PMID: 20833738]

42. Moroni G, Doria A,Mosca M, et al. Arandomized pilot tri-al comparing cy-closporine and aza-thioprine formaintenance thera-py in diffuse lupusnephritis over fouryears. Clin J Am SocNephrol. 2006;1:925-32. [PMID: 17699309]

43. Lee YH, Lee HS, ChoiSJ, et al. Efficacy andsafety of tacrolimustherapy for lupusnephritis: a system-atic review of clinicaltrials. Lupus.2011;20:636-40.[PMID: 21382917]

44. Merrill JT, NeuweltCM, Wallace DJ, et al.Efficacy and safety ofrituximab in moder-ately-to-severely ac-tive systemic lupuserythematosus: therandomized, double-blind, phase II/III sys-temic lupus erythe-matosus evaluationof rituximab trial.Arthritis Rheum.2010;62:222-33.[PMID: 20039413]

45. Rovin BH, Furie R, La-tinis K, et al; LUNARInvestigator Group.Efficacy and safety ofrituximab in patientswith active prolifera-tive lupus nephritis:the Lupus NephritisAssessment with Rit-uximab study. Arthri-tis Rheum.2012;64:1215-26.[PMID: 22231479]


heart block in neonatal SLE, hy-droxychloroquine has antithrom-botic effects that are particularlyimportant to SLE patients withantiphospholipid antibody-relatedprothrombotic diathesis (21). Hy-droxychloroquine is generally well-tolerated, and the rare risk forretinopathy is directly related tothe years of exposure to the drugand the age of the patient.

In a study of 29 cases of antimalarial reti-nal toxicity over a period of 30 years, allpatients were older than 40 years andhad had exposure to the agents over 5 years (22).

Skin hyperpigmentation and rarecases of neuromuscular or cardiactoxicity have also been reported.

How should clinicians choosetherapy for a patient who ishaving a flare?Severe SLE manifestations, such aslupus nephritis, alveolar hemor-rhage, or CNS vasculitis, should betreated with glucocorticoids admin-istered intravenously (IV) in con-junction with immunosuppressivemedications. Glucocorticoids can begradually withdrawn once remissionis achieved. Oral prednisone ormethlyprednisolone is used forarthritis, pleuropericarditis, cuta-neous vasculitis, and uveitis.

Early studies demonstrated thatglucocorticoids could ameliorateSLE, although subsequent con-trolled trials showed that the thera-peutic effect was not sustained (23).Early studies also linked glucocorti-coids to improved survival in severeSLE (24), but similar studies havenot been done for mild or moderatedisease. Current decisions aboutglucocorticoid dosage and the duration of treatment for specificmanifestations rely largely on clini-cal experience because too few clin-ical trials have been done.

An early study comparing 100 mg with 1000 mg of IV methylprednisolonesuggested that 3 daily doses of 1000 mgdid not have a significant advantage over

3 daily doses of 100 mg (25). A more recentrandomized study showed that a dose of1000 mg to 1500 mg over 3 days is as ef-fective as doses ranging from 2000 mg to5000 mg over 3 days and is associatedwith a decreased risk for infections (26).

Significant overlap exists betweenlupus manifestations and someglucocorticoid complications, in-cluding osteoporosis, avascularbone necrosis, myopathy, and psy-chosis. Furthermore, despite theabundance of observational dataon glucocorticoid toxicity, evidencefrom randomized, controlled clini-cal trials (RCTs) is limited. Table 2summarizes the 2002 EuropeanLeague Against Rheumatism rec-ommendations on glucocorticoidtreatment (27). These recommen-dations define a low daily dose ofprednisone (or equivalent) as ≤7 mg.Low doses are associated with rela-tively low risk for toxicity, althoughmonitoring for cushingoid symp-toms, osteoporosis, cataracts,glaucoma, hyperglycemia, and hy-pertension is probably justified.Prolonged treatment with mediumto high doses carries a higher riskfor complications, including my-opathy, psychosis, hyperlipidemia,and atherosclerosis. However, theprevalence and incidence of thesecomplications in different corti-costeroid regimens are still un-clear (28).

How should clinicians choose drugtherapy for cutaneous mani-festations?Commonly used topical treatmentsfor all forms of cutaneous lupus(acute, subacute, and chronic) include tacrolimus, R-salbutamolpimecrolimus, clobetasol, betametha-sone, or photoprotection. Their effi-cacy has been shown by RCTs. Suchtrials have also shown efficacy of sys-temic hydroxychloroquine or chloro-quine in cutaneous SLE. Althoughother immunosuppressive or biologicagents, such as methotrexate, my-cophenolate mofetil, azathioprine,and rituximab, may be used for cuta-neous lupus, evidence is based on



case reports or prospective, nonran-domized studies (9).

How should clinicians choose drugtherapy for lupus arthritis?Low-dose glucocorticoids and antimalarials are first-line agentsfor treating arthritis in lupus.Methotrexate is often used forarthritis or cutaneous disease, par-ticularly in patients without othersystemic manifestations.

A double-blind RCT showed that methotrex-ate is effective in controlling cutaneous andarticular symptoms in SLE (29). These find-ings were also supported by a recent open-label trial (30) and an RCT showing thatmethotrexate can be used as a steroid-sparing agent in SLE (31).

Methotrexate antagonizes folic acidand inhibits purine and pyrimidinesynthesis. In addition, it increasesextracellular adenosine release.Adenosine seems to be an importantmediator of the anti-inflammatoryeffect of methotrexate.

How should clinicians choose anddose drug therapy for lupusnephritis?Induction therapyThe indications for kidney biopsyare in the Box: Indications for Kid-ney Biopsy in Patients With SLE;the currently accepted classificationsystem for biopsy results are in theBox: Histopathologic Classificationof Lupus Nephritis.

Class I or II lupus nephritis doesnot require immunosuppressivetherapy. Class III or IV is treatedaggressively. Until recently, cyclo-phosphamide combined with intra-venous glucocorticoids has been the standard of care for inductiontherapy of class III and IV lupusnephritis. Cyclophosphamide is an alkylating agent that promotesDNA cross-linking and affects T-and B-cell proliferation and anti-body production. It is usually dosedaccording to total body surface areaand adjusted for decreased creati-nine clearance. Cyclophosphamide

toxicity includes hematologic, in-fectious, urologic, reproductive, andrare pulmonary complications andbladder, skin, myeloproliferative,and oropharyngeal cancers. To date,there is no definitive evidence fromclinical trials to guide clinicians onthe dose of glucocorticoids for in-duction therapy of lupus nephritis.Current ACR recommendationsare based on expert opinion andconsensus.

Early open-label trials and RCTs showedshort-term efficacy of glucocorticoids fortreatment of lupus nephritis. Subsequently,an RCT comparing cyclophosphamide toglucocorticoids showed superiority of cy-clophosphamide for induction therapy ofproliferative lupus nephritis. Nonresponsewas more common in the group treated withIV glucocorticoids and the probability ofachieving remission was higher in the gluco-corticoid plus cyclophosphamide group (32).

Long-term follow-up of the study partici-pants indicated that an increase in creatinineby 50% or 100% was less common in patientsreceiving combination treatment (33).

Over the past decade, several studieshave shown efficacy of mycophenolatemofetil for induction therapy in lupusnephritis (34–36). This drug is metab-olized to mycophenolic acid, an in-hibitor of inosine 5-monophosphatedehydrogenase, which is required forde novo synthesis of guanosine nu-cleotides. Mycophenolate mofetil inhibits lymphocyte proliferation, induces apoptosis of activated T-cells,and inhibits adhesion molecule ex-pression and fibroblast proliferation.Gastrointestinal toxicity is commonand may respond to dose reductionor enteric-coated formulation.Hematologic toxicity is also com-mon, ranging from mild cytopeniasto red cell aplasia. Mycophenolatemofetil is contraindicated in preg-nancy because of case reports sug-gesting teratogenicity (37).

In a meta-analysis of 4 selected RCTs eval-uating the efficacy of mycophenolatemofetil vs. cyclophosphamide for inductiontherapy, when data on maintenance thera-py were excluded mycophenolate mofetil

46. Andrade-Ortega L,Irazoque-PalazuelosF, López-VillanuevaR, et al. [Efficacy ofrituximab versus cy-clophosphamide inlupus patients withsevere manifesta-tions. A randomizedand multicenterstudy]. ReumatolClin. 2010;6:250-5.[PMID: 21794725]

47. Radhakrishnan J,Moutzouris DA, Gin-zler EM, et al. My-cophenolate mofetiland intravenous cy-clophosphamide aresimilar as inductiontherapy for class Vlupus nephritis. Kid-ney Int. 2010;77:152-60. [PMID: 19890271]

48. Spetie DN, Tang Y,Rovin BH, et al. My-cophenolate therapyof SLE membranousnephropathy. KidneyInt. 2004;66:2411-5.[PMID: 15569333]

Indications for Kidney Biopsy inPatients With SLE*Increasing serum creatinine without

compelling alternative causesConfirmed proteinuria ≥1.0 g/24 h

(either 24-h urine specimens orspot protein–creatinine ratio)

Combination of the following:Proteinuria ≥0.5 ≥1.0 g/24 h +hematuria (≥5 red bloodcells/high-power field) orproteinuria ≥0.5 ≥1.0 g/24 h +cellular casts

* From reference 38.

Histopathologic Classification ofLupus NephritisClass I: Minimal mesangialClass II: Mesangial proliferativeClass III: Focal proliferativeClass IV: Diffuse proliferative (with

active, active and chronic, orchronic lesions)

Class V: Membranous (with orwithout coexisting class III or IVlupus nephritis)

Class VI: Advanced sclerosing lupusnephritis with >90% globallysclerotic glomeruli



lupus nephritis IV, Vc, or Vd, initially treatedwith 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 azathioprineor cyclosporine for 2 (core study) and 4years. Azathioprine and cyclosporine wereequally 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 notchange significantly with either treatment;extrarenal manifestations and clinical ac-tivity decreased with both treatments (42).

Data from this study indicate thatcyclosporine and azathioprine areequally effective for maintenancetreatment of lupus nephritis andhave similar effects on blood pres-sure and renal function.

Tacrolimus, also a calcineurin in-hibitor, may be used to treat diffuseproliferative or membranous lupusnephritis. Meta-analysis of datafrom open-label trials, case–controlstudies, and RCTs showed thattacrolimus may be effective as in-duction and maintenance therapyfor lupus nephritis or in treatmentof refractory lupus nephritis withpersistent proteinuria (43).

Rituximab is a monoclonal antibodydirected against CD20, a membraneprotein expressed on B-cells. Ritux-imab depletes B-cells from the pe-ripheral blood. Open-label trials indicated improvement of lupusnephritis after B-cell depletion; how-ever, RCTs did not show statisticallysignificant response compared withplacebo (44–46).

Current ACR guidelines proposemycophenolate mofetil or azathio-prine as preferred maintenance thera-py for proliferative lupus nephritis.Calcineurin inhibitors or rituximabcombined with glucocorticoids maybe used for patients with an adequateresponse to cyclophosphamide ormycophenolate mofetil (38). To date,no RCT has directly compared cal-cineurin inhibitors to mycophenolate

mofetil for maintenance treatment ofclass III or IV lupus nephritis.

How should clinicians choose drugtherapy for membranous nephritis?Pure membranous nephritis is notassociated with endocapillary pro-liferation and presents with variabledegrees of proteinuria. The pro-gression of renal dysfunction isslow compared with that of classIII or IV lupus nephritis. The evi-dence to guide treatment of mem-branous lupus nephritis is limited.

A retrospective analysis of 2 large RCTsshowed similar efficacy of mycophenolatemofetil and cyclophosphamide for induc-tion therapy of class V lupus nephritis (47).

A prospective study of mycophenolatemofetil combined with renoprotective ther-apy (with angiotensin inhibitors or an-giotensin-receptor blockers) showed thatmost patients achieved complete or partialremission at 6 months and sustained effectfor a mean follow-up of 18 months (48).

Based on this evidence, currentguidelines from the ACR for mem-branous lupus nephritis recommendtreatment with mycophenolatemofetil. Tacrolimus and azathio-prine have also been studied for in-duction or maintenance treatment.

A recent open-label trial showed thattacrolimus or mycophenolate mofetil com-bined with steroids were both effective in con-trolling membranous lupus nephritis (49).

An RCT comparing azathioprine withtacrolimus, both combined with pred-nisone, for maintenance therapy of mem-branous nephritis suggests similar lowrates in relapse with both regimens (50).

How should clinicians choosetherapy for neuropsychiatriclupus?Treatment of serious neuropsychi-atric SLE manifestations is rela-tively empirical and includes IVglucocorticoids, immunoglobulin,and cyclophosphamide.

An RCT comparing cyclophosphamidewith glucocorticoids after 3 days of IV im-munoglobulin for treatment of transverse

was not superior to cyclophosphamide inlupus nephritis (36).

Recently updated guidelines rec-ommend using either cyclophos-phamide or mycophenolate mofetilcombined with glucocorticoids forinduction therapy of class III orIV proliferative lupus nephritis(38). Response to cyclophos-phamide or mycophenolate mofetilmay differ based on race. Asiansand Europeans seem to respondbetter to cyclophosphamide thanHispanics and African Americans(38).

Maintenance therapyCurrent guidelines recommend either mycophenolate mofetil or aza-thioprine for maintenance therapy inlupus nephritis. Both are superior tocyclophosphamide for this purpose(39). Evidence from 2 studies ofcomparative efficacy of mycopheno-late mofetil vs. azathioprine is con-flicting (40, 41). Treatment durationis 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 eithercyclophosphamide or mycophenolatemofetil, patients were randomly assigned totreatment with mycophenolate mofetil (2 g/d) or azathioprine (2 mg/kg/d). After 3years of follow up, mycophenolate mofetilwas significantly superior to azathioprinewith respect to time to treatment failure (pri-mary end point), time to renal flare, andtime to rescue therapy (40).

In contrast, an open-label study showedno significant difference in patients treatedwith mycophenolate mofetil vs. azathio-prine for maintenance treatment of lupusnephritis over a period of 4 years. All patients in the study were initially treatedwith 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 trialcompared the efficacy of cyclosporine vs.azathioprine for maintenance therapy oflupus nephritis. Seventy-five patients with



myelitis in lupus showed that relapse wasmore common in the steroid group (51).

Case reports and small, uncon-trolled studies suggest a beneficialeffect of rituximab in treatment ofneuropsychiatric lupus; however,the relapse rate seems to be high.

How should clinicians choosetherapy for respiratorymanifestations?Pleuritis responds to treatment withNSAIDs and low to moderate dos-es of glucocorticoids. Immunosup-pressive treatment is reserved for refractory cases. Diffuse alveolarhemorrhage presents abruptly, car-ries a poor prognosis, and requirestreatment with IV glucocorticoidsand immunosupressants. Plasma-pheresis may also be considered.Pulmonary hypertension is rare inSLE (0.5–17%) and may be sec-ondary to vasculopathy, interstitialpulmonary fibrosis, or in situthrombosis (52). SLE patients withpulmonary hypertension are at highrisk for cardiac failure and earlydeath. Endothelin-receptor antago-nists, phosphodiesterase-5 in-hibitors, and prostacyclin analogswith or without immunosuppressivemedications may be used to treatpulmonary hypertension in lupus.

An RCT showed efficacy of cyclophos-phamide in mild and moderate pul-monary hypertension in patients with SLEby reducing pulmonary artery systolicpressure and improving the New YorkHeart Association functional class (53).

A retrospective study suggests that patientswith SLE and mild to moderate pulmonaryhypertension may respond to treatment withcyclophosphamide and glucocorticoids,while patients with more severe disease mayrequire combination of vasodilators with im-munosuppressants (54).

A small study indicated that interstitiallung disease treated with glucocorticoidsfor at least 1 week resulted in indolent pro-gression or stabilization over time (55).

Larger clinical trials have not beendone, and treatment decisions are based on clinical experience.

Azathioprine or cyclophosphamideis frequently recommended for pa-tients who have not responded toglucocorticoids (56). Acute lupuspneumonitis requires treatmentwith high doses of glucocorticoidsand cyclophosphamide.

How should clinicians choosetherapy for ocular manifestations?Depending on the severity of theocular involvement and the activityof the systemic disease, treatmentmay include antimalarial agents,NSAIDs, or oral or IV glucocorti-coids. Scleral or retinal involvementmay require concomitant use ofpulse glucocorticoids, followed by 1 mg/kg of prednisone equivalent,combined with immunosuppressivetherapy (57). Retinal vasculitis andarterial or venous retinal occlusionin the presence of antiphospholipidantibodies may require concomitantuse of immunosuppressive medica-tions and antiplatelet agents or an-ticoagulation.

What new medications areavailable for treating systemiclupus?A monoclonal antibody targetingthe B-lymphocyte stimulator(BLys) was recently approved.

Two international, double-blind, phase 3RCTs compared belimumab 1 mg/kg and10 mg/kg plus standard therapy to pla-cebo plus standard therapy (58, 59). In the52-week study, reduction of ≥4 points onthe SLE Response Index (SRI) was 51% and58% with the belimumab 1-mg/kg and 10-mg/kg dose, respectively, vs. 44% withplacebo (P<0.05). In the 76-week study, theSRI-measured response at 52 weeks was42.8% and 46.5% with the belimumab 1-mg/kg and 10-mg/kg dose and 35.3%with placebo; at 76 weeks, the responserates were 42.1% and 41.4% with the beli-mumab 1-mg/kg and 10-mg/kg dose, and33.8% with placebo (P<0.05 and P = NS, re-spectively). Both trials excluded patientswith severe lupus nephritis or severe CNSmanifestations. Analysis of combined re-sults from both trials showed more improvement of musculoskeletal and mu-cocutaneous manifestations in patientstreated with belimumab and improvement

49. Yap DY, Yu X, ChenXM, et al. Pilot 24month study tocompare mycophe-nolate mofetil andtacrolimus in thetreatment of mem-branous lupusnephritis withnephrotic syndrome.Nephrology (Carl-ton). 2012;17:352-7.[PMID: 22295934]

50. Chen W, Liu Q, ChenW, et al. Outcomesof maintenancetherapy withtacrolimus versusazathioprine for ac-tive lupus nephritis:a multicenter ran-domized clinical trial.Lupus. 2012;21:944-52. [PMID: 22438027]

51. Kovacs B, Lafferty TL,Brent LH, et al. Trans-verse myelopathy insystemic lupus ery-thematosus: ananalysis of 14 casesand review of the lit-erature. Ann RheumDis. 2000;59:120-4.[PMID: 10666167]

52. Dhala A. Pulmonaryarterial hypertensionin systemic lupuserythematosus: cur-rent status and fu-ture direction. ClinDev Immunol.2012;2012:854941.[PMID: 22489252]

53. Gonzalez-Lopez L,Cardona-Muñoz EG,Celis A, et al. Therapywith intermittentpulse cyclophos-phamide for pul-monary hyperten-sion associated withsystemic lupus ery-thematosus. Lupus.2004;13:105-12.[PMID: 14995003]

54. Jais X, Launay D,Yaici A, et al. Im-munosuppressivetherapy in lupus-and mixed connec-tive tissue disease-associated pul-monary arterialhypertension: a ret-rospective analysisof twenty-three cas-es. Arthritis Rheum.2008;58:521-31.[PMID: 18240255]

55. Weinrib L, SharmaOP, Quismorio FP Jr.A long-term study ofinterstitial lung dis-ease in systemic lu-pus erythematosus.Semin ArthritisRheum. 1990;20:48-56. [PMID: 2218553]


56. Pego-Reigosa JM,Medeiros DA, Isen-berg DA. Respiratorymanifestations ofsystemic lupus ery-thematosus: old andnew concepts. BestPract Res ClinRheumatol.2009;23:469-80.[PMID: 19591778]

57. Neumann R, FosterCS. Corticosteroid-sparing strategies inthe treatment ofretinal vasculitis insystemic lupus ery-thematosus. Retina.1995;15:201-12.[PMID: 7569347]

58. Furie R, Petri M, Za-mani O, et al; BLISS-76 Study Group. Aphase III, random-ized, placebo-con-trolled study of beli-mumab, amonoclonal anti-body that inhibits Blymphocyte stimula-tor, in patients withsystemic lupus ery-thematosus. ArthritisRheum.2011;63:3918-30.[PMID: 22127708]

59. Navarra SV, GuzmánRM, Gallacher AE, etal; BLISS-52 StudyGroup. Efficacy andsafety of belimumabin patients with ac-tive systemic lupuserythematosus: arandomised, place-bo-controlled, phase3 trial. Lancet.2011;377:721-31.[PMID: 21296403]

60. van Vollenhoven RF,Petri MA, Cervera R,et al. Belimumab inthe treatment of sys-temic lupus erythe-matosus: high dis-ease activitypredictors of re-sponse. Ann RheumDis. 2012;71:1343-9.[PMID: 22337213]

61. Tseng CE, Buyon JP,Kim M, et al. The ef-fect of moderate-dose corticosteroidsin preventing severeflares in patientswith serologically ac-tive, but clinicallystable, systemic lu-pus erythematosus:findings of aprospective, ran-domized, double-blind, placebo-con-trolled trial. ArthritisRheum.2006;54:3623-32.[PMID: 17075807]

62. Mok CC, Ho LY, FongLS, To CH. Immuno-genicity and safetyof a quadrivalent hu-man papillomavirusvaccine in patientswith systemic lupuserythematosus: acase-control study.Ann Rheum Dis.2013;72:659-64.[PMID: 22589375]


in immunologic parameters; in addition,fewer patients had worsening hematologicparameters (60).

The SRI requires reduction indisease activity scores and no de-terioration from baseline in targetorgan manifestations (58). Fur-ther evidence is needed to assessthe comparative efficacy of BlySantagonism in severe lupus mani-festations.

How should clinicians monitorpatients who are being treated forlupus?Laboratory testing should includea complete blood count, basicmetabolic panel, and urinalysis onroutine follow-up visits. Thesetests allow the clinician to evalu-ate for hematologic, renal, andother target-organ manifestations.Many clinicians also routinely testfor double-stranded DNA anti-bodies and complement C3 andC4 levels; however, this practice iscontroversial for clinically stablepatients. Although a prospectiveRCT showed that 4-week treatment with prednisone of clin-ically stable but serologically ac-tive patients averts a severe flare(61), C3 and C4 and double-stranded DNA antibodies aremore useful in assessing SLE ac-tivity in symptomatic patients orin assessing response to treatment.Other monitoring should be tai-lored to individual disease mani-festations (Table 3). Considerationshould be given to laboratorymonitoring for immunosuppres-sive medication toxicity and oph-thalmologic evaluation of patientstreated with hydroxychloroquine,particularly those older than 40 years who have been treated fora long period. Clinicians should bealert to osteoporosis preventionand prescribe treatment when ap-propriate. Clinicians should alsoconsider periodic lipid testing andorder lipid-lowering agents, asneeded.

What should clinicians do aboutimmunizations in people withlupus?All patients with SLE should re-ceive influenza and pneumococcalvaccinations. In addition, a recentstudy showed that the quadrivalenthuman papillomavirus vaccine iswell-tolerated and reasonably ef-fective in patients with stable SLEand does not induce an increase inlupus activity or flares (62). Pa-tients receiving immunosuppres-sive therapy or daily prednisone>20 mg should not receive live at-tenuated vaccines, including her-pes zoster (shingles), Flumist,measles-mumps-rubella, andsmallpox. Tuberculin skin testingis recommended for SLE patientsrequiring prolonged treatmentwith glucocorticoids or immuno-suppressive therapy.

How should clinicians modifytreatment for pregnant patients?Fertility is not significantly af-fected in SLE; however, flares occur at a higher rate duringpregnancy and the immediatepostpartum period. The presenceof anti-SSA antibodies may pre-dict adverse pregnancy outcomes,as may other factors, includingantiphopsholipid antibodies, renaldisease, thrombocytopenia, hyper-tension, and use of prednisone.Becoming pregnant during clini-cal remission correlates with lessfrequent and severe lupus exacer-bations. The initial presentationof SLE with hematologic or renalmanifestations during pregnancyis not uncommon. Cliniciansshould also consider pregnancy-related hematologic, vascular, andrenal abnormalities that mimicSLE manifestations, includingeclampsia and the HELLP syn-drome (a group of symptoms thatoccurs in pregnant women withhemolysis, elevated liver enzymes,and low platelet counts). Anti-malarials can be used safely inpregnant SLE patients (63). Active lupus manifestations in



pregnancy are usually treated withhydroxychloroquine and pred-nisone. It is advisable to continuehydroxychloroquine in pregnancybecause discontinuation is associ-ated with increased risk for flaresand pregnancy is associated withrisk for increased disease activity.Hydroxychloroquine may alsoprotect against cardiac manifesta-tions of neonatal lupus.

For severe manifestions, IV gluco-corticoids and azathioprine may beconsidered because azathioprinehas not been identified as a humanteratogen (64). Mycophenolatemofetil, cyclophosphamide, andmethotrexate are contraindicateddue to potential teratogenicity.

When should patients with lupusbe hospitalized?Patients with serious complica-tions should be hospitalized. Indications include severe throm-bocytopenia, severe or rapidly pro-gressive renal disease, suspectedlupus pneumonitis or pulmonaryhemorrhage, and severe cardiovas-cular or CNS manifestations. Amajor cause of death in SLE is in-fection, including from oppor-tunistic pathogens. SLE patientswith unexplained fever should behospitalized for evaluation andinitiation of treatment with antibi-otics. Empirical coverage shouldinclude Staphyloccocus aureus,Pseudomonas species, Klebsiellaspecies, Escherichia coli, and Acineto-bacter species. Chest pain in lupuspatients could be due to coronaryartery disease, serositis, pulmonaryembolism, or esophageal disease.Lupus increases the risk for en-dothelial dysfunction, and long-termtreatment with steroids increasestraditional risk factors for coronaryartery disease (65). Neurologicsymptoms in lupus patients maybe due to neuropsychiatric lupus,infection, the antiphospholipidsyndrome, or hypertension. All lu-pus patients with acute neurologicmanifestations should be admitted

and rapidly evaluated with appro-priate imaging, cerebrovascularfluid analysis, echocardiogram, andlaboratory studies.

When should clinicians considerconsulting a rheumatologist orother specialist?A rheumatologist should be in-volved in the treatment of all lupuspatients (66). Other specialists alsomay be involved, according to or-gan-specific disease manifestations.

What nondrug therapies shouldclinicians recommend?All lupus patients should becounseled on low-cholesterol diet,

Table 3. Recommended Follow-up of Patients With SLEIssue How Frequency

Disease activity History (rash, joint pain Quarterlyconstitutional symptoms); physical examination; CBC, urinalysis, CMP

Nephropathy CMP, urinalysis, urine protein– Quarterly, if inactive disease, creatinine ratio or monthly, to assess response

to treatment

Hyperlipidemia Fasting lipid profile Yearly

Hydroxychloroquine toxicity History (visual disturbances); Yearlyophthalmologic evaluation

MMF, AZA toxicity CBC, CMP Every 8–12 wk or 4 wk after change in dose

Cervical dysplasia on Gynecologic examination; Yearlyimmunosuppressants PAP smear, HPV test

Osteonecrosis History, x-rays or MRI of With symptoms and history affected joint suggestive of avascular necrosis

Thrombosis History, examination venous With symptoms or signs duplex studies, imaging for suggestive of thrombosispulmonary embolism

Pulmonary hypertension Echocardiography Yearly, or as clinically indicated

Osteoporosis DEXA Every 1–2 years, while on steroids

Planned pregnancy Antiphospholipid antibodies Before conceptionurinalysis, anti-SSA/SSB antibodies, CBC, CMP, and complement C3 and C4

Patient education Every visit

AZA = azathioprine; CBC = complete blood count; CMP = comprehensive metabolic panel; DEXA = dual x-ray absorptiometry; HPV= human papillomavirus; MMF = mycophenolate mofetil; MRI = magnetic resonance imaging; PAP = Papanicolaou.

63. Costedoat-Chalumeau N,Amoura Z, Duhaut P,et al. Safety of hy-droxychloroquine inpregnant patientswith connective tis-sue diseases: a studyof one hundred thir-ty-three cases com-pared with a controlgroup. ArthritisRheum.2003;48:3207-11.[PMID: 14613284]

64. Natekar A, Pupco A,Bozzo P, Koren G.Safety of azathio-prine use duringpregnancy. Can FamPhysician.2011;57:1401-2.[PMID: 22170192]


65. Petri M, Lakatta C,Magder L, et al. Ef-fect of prednisoneand hydroxychloro-quine on coronaryartery disease riskfactors in systemiclupus erythemato-sus: a longitudinaldata analysis. Am JMed. 1994;96:254-9.[PMID: 8154514]

66. Gabriel S, Tugwell P,O’Brien B, et al. Re-port of the OMER-ACT task force oneconomic evalua-tion. OutcomeMeasures inRheumatology. JRheumatol.1999;26:203-6.[PMID: 9918264]

Inthe

C linicTool Kit

In the Clinic

Systemic LupusErythematosus

PIER Modulehttp://smartmedicine.acponline.org/content.aspx?gbosId=153

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

Patient Informationwww.nlm.nih.gov/medlineplus/lupus.htmlwww.nlm.nih.gov/medlineplus/tutorials/lupus/htm/index.htmwww.nlm.nih.gov/medlineplus/spanish/tutorials/lupusspanish/

htm/index.htmResources related to lupus from the National Institutes of Health’s

MedlinePLUS, including an interactive tutorial in English andSpanish.

www.niams.nih.gov/Health_Info/Lupus/lupus_ff.aspwww.niams.nih.gov/Portal_En_Espanol/Informacion_de_Salud/Lupus/

default.aspAnswers to common questions about lupus from the National Institute

of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), inEnglish and Spanish.

www.nlm.nih.gov/medlineplus/ency/article/000481.htmInformation about lupus nephritis, a complication of SLE from

NIAMS.

Clinical Guidelineswww.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 Criteriapier.acponline.org/physicians/diseases/d208/tables/d208

-tlab.htmlList of laboratory and other studies for SLE from PIER.www.rheumatology.org/practice/clinical/position/ana_position

_stmt.pdfPosition statement on the methodology of testing for antinuclear

antibodies from the ACR in 2011.

1 October 2013Annals of Internal MedicineIn the ClinicITC4-14© 2013 American College of Physicians

Treatment... Hydroxychloroquine prevents disease flares and is considered thecornerstone of SLE treatment. Glucocorticoids are first-line agents for most SLEmanifestations, with dosage and treatment duration based on clinical experienceand consensus. Immunosuppressive treatment in lupus nephritis is based onhistopathologic classification and guided by ACR recommendations. Treatment ofother lupus manifestations is based on sparse evidence from clinical trials andclinical experience and often requires immunosuppressive therapy and a multidis-ciplinary approach.


such as osteoporosis or the Sjogrensyndrome, is also recommended. Allpatients should be counseled on thedaily requirements for calcium andvitamin D to prevent osteoporosis.Routine dental evaluation is alsorecommended.

exercise, weight control, and smok-ing cessation. They should also beadvised about protection from ultra-violet rays to reduce flares from sunexposure. Prevention or treatment ofcomplications due to conditionscommonly associated with lupus,


In the ClinicAnnals of Internal Medicine

Pati

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Info

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THINGS YOU SHOULDKNOW ABOUT LUPUS

What is lupus?• A chronic disease that occurs when the body’s de-

fense system (the immune system) wrongly attacksits 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 fluctuatebetween 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 womenthan 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 ovalpatches).

• 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) orthe 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.

• Antimalarial drugs (such as hydroxychloroquine) toreduce fatigue, rashes, joint pain, and mouth sores.

• Corticosteroids or biologics, a new type of drug forrheumatic diseases, to reduce inflammation.

• Treatment is based on the symptoms and the severityof the disease.

For More Information

www.niams.nih.gov/Health_Info/Lupus/default.aspBooklet 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.


CME Questions

1 October 2013Annals of Internal MedicineIn the ClinicITC4-16© 2013 American College of Physicians

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.

1. A 25-year-old woman is evaluated for a1-year history of scaly plaques on herface and scalp. Results of a skin biopsy 1 week ago are consistent with chroniccutaneous lupus. She has ongoing mildfatigue, a 10-day history of lower backpain, and occasional migraine headachesfor which she takes sumatriptan asneeded. She also has a history of partial-onset seizures that began at age 13 yearsfor which she currently takes phenytoin.

On physical examination, temperature is37.0°C (98.6°F), blood pressure is 125/73 mm Hg, pulse rate is 72/min, andrespiration rate is 16/min. Cutaneousexamination reveals scattered circularplaques on the cheeks, nose, scalp, andear canals. Within the plaques, there isfollicular plugging and atrophic scarring.She also has patches of alopecia wherethe rash is present on the scalp.Cardiopulmonary examination is normal.There is no lymphadenopathy or oralulcers. Abdominal examination isunremarkable. Musculoskeletalexamination reveals no synovitis, andneurologic examination is normal.

Laboratory studies reveal the following:hemoglobin, 14 g/dL (140 g/L); leukocytecount, 6300/µL (6.3 × 109/L); erythrocytesedimentation rate, 16 mm/h; serumcreatinine, 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; antiribonucleoproteinantibodies, negative; antihistoneantibodies, negative; urinalysis, normal.

Which of the following is the most likelydiagnosis?

A. Discoid lupusB. Drug-induced lupusC. Mixed connective tissue diseaseD. Systemic lupus erythematosus

2. A 28-year-old woman with systemiclupus erythematosus (SLE) is evaluated inthe office after obtaining positive resultson a home pregnancy test. She has a 1-month history of nausea but isotherwise asymptomatic. Her lastmenstrual period was 2 months ago. Thisis her first pregnancy. Her SLE is well-controlled with hydroxychloroquine, andher last flare was 10 months ago.

On physical examination, temperature is36.2°C (97.2°F), blood pressure is 110/72 mm Hg, pulse rate is 76/min, and respiration rate is 16/min. Physicalexamination is normal. A repeatedpregnancy 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 herSLE during her pregnancy.

Which of the following is the mostappropriate management of this patient?

A. Discontinue hydroxychloroquineB. Recommend termination of pregnancyC. Start prednisoneD. No change in management

3. A 43-year-old woman with SLE isadmitted to the hospital for a 1-weekhistory of worsening headache and a 2-day history of confusion, personalitychange, and emotional lability. She wasdiagnosed with lupus 1 year ago, and hercondition has been well-controlled withprednisone, hydroxychloroquine, andibuprofen. Four months ago, prednisonewas discontinued.

Two months ago, she developed fatigue,intermittent low-grade fevers, and

occasional headache. Two weeks ago, shewas evaluated in the office for a 1-month history of purpuric lesions onher legs, palms, and soles. Biopsyspecimen of a lesion showedleukocytoclastic vasculitis. At that time,prednisone, 40 mg/d, was initiated, andthe purpuric lesions began to fade.

On physical examination today,temperature is 37.9°C (100.2°F), bloodpressure is 150/80 mm Hg, pulse rate is102/min, and respiration rate is 20/min.The purpuric lesions persist. She isconfused and oriented to name only,intermittently laughs and cries, and hasparanoid ideation. She does not havephotophobia or nuchal rigidity, and theneurologic 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 brainreveals scattered punctate areas ofincreased signal in the periventricularand subcortical white matter.

Which of the following is the mostappropriate next step in this patient’streatment?

A. Begin ampicillin and gentamicinB. Begin methylprednisolone and

cyclophosphamideC. Discontinue ibuprofenD. Schedule plasmapheresis


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