cpg sle

ARTHRITIS & RHEUMATISMVol. 42, No. 9, September 1999, pp 1785–1796© 1999, American College of Rheumatology

SPECIAL ARTICLE

GUIDELINES FOR REFERRAL AND MANAGEMENT OFSYSTEMIC LUPUS ERYTHEMATOSUS IN ADULTS

AMERICAN COLLEGE OF RHEUMATOLOGY AD HOC COMMITTEE ONSYSTEMIC LUPUS ERYTHEMATOSUS GUIDELINES

Introduction

Systemic lupus erythematosus (SLE) is a chronicinflammatory autoimmune disease of unknown etiology,with protean manifestations and a variable course andprognosis. SLE is a complex disorder that affects pri-marily women in their childbearing years. It is charac-terized by periods of relative quiescence and periods ofexacerbations, which may involve any organ or system invarious combinations (1–10) (Tables 1 and 2). Patientswith SLE develop distinct immunologic abnormalities, inparticular, antinuclear, anticytoplasmic, and antiphos-pholipid antibodies. Genetic, immunologic, hormonal,and environmental factors are involved in its pathogen-esis (1–10). The prevalence of SLE is 1:1,000; thus, mostprimary care physicians and general internists will nothave sufficient experience in the management of mod-erate or severe life-threatening disease.

In addition to the persistent risk of disease flares,more than one-half of SLE patients develop permanentorgan system damage (11). This damage progresses overtime and is usually more severe in African Americanpatients than in white patients (12). Although the prog-nosis of SLE has improved dramatically in the last 4decades, mortality remains a major concern. The mor-tality rate among patients with SLE is at least 3 timesthat of the general population (13). Survival rates are;80% at 10 years after diagnosis and ;65% at 20 years(1–8,13–16). Deaths early in the course of SLE areusually attributed to active disease and infections, butdeaths that occur later in the disease course are oftendue to atherosclerotic vascular disease (14). Therapy,especially long-term high-dose glucocorticoid treatment,can contribute to myopathy, osteoporosis, hypertension,diabetes, atherosclerotic vascular disease, infections,and death. Timely and aggressive therapy, however, candelay or prevent morbidity and organ failure and is costeffective (17).

SLE is a systemic illness with multiple end-organinvolvement. As such, it challenges both the patients andtheir families. Patients with newly diagnosed SLE oftenhave anxieties about a possibly fatal chronic illness withunpredictable flares and potential disability; these anxi-eties should be addressed. Patients must learn how tocope with and monitor their own disease and to assist thephysician in distinguishing coincident unrelated symp-toms from signs and symptoms of a flare. Psychologicalsupport by either the physician and/or an appropriatehealth professional is essential. SLE patients may needthe expertise of professionals in the fields of social work,vocational counseling, psychology, physical and occupa-tional therapy, ophthalmology, dermatology, nephrol-

Members of the Ad Hoc Committee on Systemic LupusErythematosus Guidelines are as follows. Dafna D. Gladman, MD(chair), Murray B. Urowitz, MD: The Toronto Hospital and Universityof Toronto, Toronto, Ontario, Canada; John M. Esdaile, MD, MPH:Mary Pack Arthritis Centre and Vancouver Hospital, Vancouver,British Columbia, Canada; Bevra H. Hahn, MD: University of Cali-fornia, Los Angeles; John Klippel, MD: National Institute of Arthritisand Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland;Robert Lahita, MD, PhD: Saint Vincent’s Medical Center, New York,New York; Matthew H. Liang, MD, MPH, Peter Schur, MD: Brighamand Women’s Hospital, Boston, Massachusetts; Michelle Petri, MD,MPH: Johns Hopkins Hospital, Baltimore, Maryland; Daniel Wallace,MD: Cedars–Sinai Medical Center/University of California, Los An-geles, School of Medicine.

The American College of Rheumatology is an independentprofessional, medical, and scientific society which does not guarantee,warrant, or endorse any commercial product or service.

Address reprint requests to American College of Rheumatol-ogy, 1800 Century Place, Suite 250, Atlanta, GA 30345.

Submitted for publication January 29, 1999; accepted inrevised form May 18, 1999.

Arthritis & RheumatismOfficial Journal of the American College of Rheumatology

1785

ogy, cardiology, orthopedic surgery, and other disci-plines. Not all of these are needed at any one time, andtheir coordination is best done by a specialist, usually arheumatologist, who has experience in following uppatients with SLE and knows what value is added fromthese consultants.

These guidelines for the management of SLEwere prepared to improve the quality of care for SLEpatients by primary care physicians. They are based onavailable evidence-based information for the diagnosisand management of the disease. Where such evidence is

unavailable, the guidelines are based on the recommen-dations of SLE specialists. While the members of theAmerican College of Rheumatology Ad Hoc Committee

Figure 1. Tasks of the primary care physician in the diagnosis andmanagement of systemic lupus erythematosus (SLE).

Table 1. Clinical features of systemic lupus erythematosus

System Features

Constitutional FatigueFever (in the absence of infection)Weight loss

Musculoskeletal Arthritis, arthralgiaMyositis

Skin Butterfly rashPhotosensitivityMucous membrane lesionAlopeciaRaynaud’s phenomenonPurpuraUrticariaVasculitis

Renal HematuriaProteinuriaCastsNephrotic syndrome

Gastrointestinal Nausea, vomitingAbdominal pain

Pulmonary PleurisyPulmonary parenchymaPulmonary hypertension

Cardiac PericarditisEndocarditisMyocarditis

Reticuloendothelial LymphadenopathySplenomegalyHepatomegaly

Hematologic AnemiaThrombocytopeniaLeukopenia

Neuropsychiatric PsychosisSeizuresOrganic brain syndromeTransverse myelitisCranial neuropathiesPeripheral neuropathies

Table 2. Frequency of serologic abnormalities in systemic lupuserythematosus*

AbnormalityAt onset,

%At any time,

%

Antinuclear antibodies 76 94

Antibodies toDouble-stranded DNA 34 71Sm 31 49RNP 21 35Ro/SSA 33 67La/SSB 27 49

Low complement 44 77

* From ref. 5.

1786 ACR COMMITTEE ON SLE GUIDELINES

on SLE Guidelines were rheumatologists who are ex-perts in the care of patients with SLE, the guidelineswere reviewed by primary care physicians who concurredwith their content.

The 4 major tasks of the primary care physician inthe diagnosis and management of SLE (Figure 1) are 1)to be alert to the possibility of SLE in their patients, andto make a diagnosis as early as possible; 2) to manageand monitor patients with SLE who have mild and stabledisease (i.e., those without major organ involvementand/or comorbidity); 3) to recognize when referral to a

rheumatologist is indicated; and 4) to collaborate withthe specialist in monitoring disease activity and therapyin patients with moderate to severe SLE.

Initial evaluation: making the diagnosis

Because of its multisystem involvement and itsprotean manifestations, the diagnosis of SLE may bedifficult. SLE should be suspected in any patient who hasfeatures affecting 2 or more organ systems as listed inTable 1. The American College of Rheumatology has

Table 3. 1997 update of the 1982 American College of Rheumatology classification criteria for systemic lupus erythematosus*

Item Definition

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

Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging: atrophic scarring mayoccur in older lesions

Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation

Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician

Nonerosive arthritis Involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion

Pleuritis or pericarditis a. Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusionOR

b. Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion

Renal disorder a. Persistent proteinuria .0.5 gm per day or .31 if quantitation not performedOR

b. Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed

Neurologic disorder a. Seizures—in the absence of offending drugs or known metabolic derangement, e.g., uremia,ketoacidosis, or electrolyte imbalance

ORb. Psychosis—in the absence of offending drugs or known metabolic derangement, e.g., uremia,

ketoacidosis, or electrolyte imbalance

Hematologic disorder a. Hemolytic anemia with reticulocytosisOR

b. Leukopenia—,4,000/mm3 on $2 occasionsOR

c. Lymphopenia—,1,500/mm3 on $2 occasionsOR

d. Thrombocytopenia—,100,000/mm3 in the absence of offending drugs

Immunologic disorder a. Anti-DNA: antibody to native DNA in abnormal titerOR

b. Anti-Sm: presence of antibody to Sm nuclear antigenOR

c. Positive finding of antiphospholipid antibodies based on: 1) an abnormal serum level of IgG or IgManticardiolipin antibodies, 2) a positive test result for lupus anticoagulant using a standard method, or 3)a false-positive test result for at least 6 months and confirmed by Treponema pallidum immobilization orfluorescent treponemal antibody absorption test

Positive antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point intime in the absence of drug

* From ref. 10.

SLE REFERRAL AND MANAGEMENT GUIDELINES 1787

published criteria for the classification of patients ashaving SLE (9,10), shown in Table 3. Although thecriteria were designed to ensure that SLE patientsreported in the literature do in fact have the disease,they are also useful in evaluating individual patients. If apatient has, at any time in his or her medical history, 4 ofthe 11 criteria documented, the diagnosis of SLE can bemade with ;95% specificity and 85% sensitivity (18,19).If the patient meets fewer than 4 criteria, the diagnosisof SLE is possible (for example, a young woman withnephritis, antinuclear antibodies [ANA], and anti-DNAmeets only 3 criteria but almost surely has SLE), and thediagnosis depends upon clinical judgment. If ANA arenegative, the patient has a very low probability of havingSLE. Patients with positive ANA alone, without organsystem involvement or typical laboratory findings, areunlikely to have SLE (20).

Other serologic tests may have a higher predic-tive value than ANA, and thus may aid in the diagnosisof SLE or related connective tissue disease. High-titerIgG antibodies to double-stranded DNA (dsDNA) andantibodies to the Smith antigen (anti-Sm) are usuallyspecific for SLE. Antibodies to RNA proteins (anti-RNP, anti-Ro, anti-La) and to phospholipids (anticar-diolipin) occur in SLE and other connective tissuediseases, as does hypocomplementemia (18,21). Thefrequencies at which these serologic abnormalities occurin SLE are listed in Table 2.

A number of other diseases may be confused withearly SLE because they present with either clinical orlaboratory features that may be similar to those seen inSLE. These include undifferentiated connective tissuedisease, primary Sjogren’s syndrome, primary antiphos-pholipid syndrome, fibromyalgia with positive ANA,idiopathic thrombocytopenic purpura, drug-induced lu-pus, and early rheumatoid arthritis (22) (Table 4). SLEcan be mild, moderate, or severe. Almost all patientswith anything more than stable mild symptoms should becared for by an experienced physician, who, in mostcases, will be a rheumatologist. Many SLE patients may

also prefer to have their specialist act as principal careprovider to manage and coordinate their general healthcare. At any one time, one or more organ systems maybe affected by SLE. Patients with mild SLE are thosewho 1) clearly have the diagnosis, 2) are clinically stable,3) do not have life-threatening disease, and 4) havestable normal function of body systems that can bedamaged by SLE, such as kidneys, skin, joints, hemato-logic system, lung, heart, gastrointestinal (GI) tract, andcentral nervous system (CNS). In addition, the patientshould have no significant toxicities from therapies forSLE. This definition of mild SLE is reviewed in Table 5.

Referral

We recommend referral to a rheumatologistand/or other appropriate specialist for the followingpurposes (Figure 1 and Table 6).

Establishment of the diagnosis. Patients in whomSLE is suspected based on history, physical examinationresults, or laboratory data should be referred to arheumatologist to establish or confirm the diagnosis,particularly if there are symptoms, signs, or laboratoryevidence of disease that suggest more than mild SLE(Table 5). As noted above, diagnosis can be difficultbecause of multisystem involvement and variability of

Table 4. Conditions that may be confused with systemic lupuserythematosus

Undifferentiated connective tissue diseaseSjogren’s syndromeAntiphospholipid antibody syndromeFibromyalgia with positive antinuclear antibodyIdiopathic thrombocytopenia purpuraDrug-induced lupusEarly rheumatoid arthritisVasculitis

Table 5. Characteristics of patients with mild systemic lupuserythematosus (SLE)

1. Diagnosis of SLE is confirmed or highly suspected.2. Disease is clinically stable.3. Disease is not life-threatening.4. Body systems that can be a target of SLE have normal and stable

function, includinga. Kidneysb. Skinc. Jointsd. Hematologic systeme. Lungsf. Heartg. Gastrointestinal systemh. Central nervous system

5. There are not significant toxicities of the therapies for SLE.

Table 6. Reasons for referral to a rheumatologist

1. To confirm a diagnosis2. To assess disease activity and severity3. To provide general disease management4. To manage uncontrolled disease5. To manage organ involvement or life-threatening disease6. To manage/prevent treatment toxicities7. In other specific circumstances, including antiphospholipid

syndrome, pregnancy, surgery


presentation of the disease. Thus, in most cases, arheumatologist may be needed to interpret laboratoryfindings and confirm the diagnosis.

Assessment of disease activity and severity. As-sessment of disease activity and severity is important forthe establishment of an appropriate treatment programfor an individual patient. Since patients with very activeand severe disease are likely to require ongoing care bya rheumatologist, it is necessary to assess both theactivity and the severity of the disease early on. Vali-dated indices have been developed for the assessment ofboth disease activity and disease severity (15,23).

Establishment of a plan for disease management.A patient with established SLE may be referred to anappropriate specialist to establish a treatment plan thatmay then be followed by the primary care physician if thedisease remains stable and mild. SLE patients may bereferred to a rheumatologist to monitor efficacy and toxi-city of treatment (e.g., antimalarial drugs, glucocorticoids,and immunosuppressive/cytotoxic drugs) or to providepatient education. In addition, the rheumatologist may beasked to coordinate care with allied health professionalsand other medical specialists. Patients for whom compli-cated management decisions are necessary should be re-ferred to a rheumatologist or other appropriate specialistdepending on the major organ system involved. Examplesof such complicated management decisions are the re-quirement for long-term glucocorticoid therapy to controlthe disease; prevention of the development of complica-tions from glucocorticoid therapy or planning treatment ofthose complications; the need to consider therapy with sexhormones, antimalarial agents, or immunosuppressive/cytotoxic drugs; and consideration of investigational treat-ment modalities such as apheresis, intravenous gammaglobulin, dapsone, dehydroepiandrosterone (DHEA), andnew experimental therapies.

Management of uncontrolled disease. In patientswhose SLE manifestations persist despite therapy, consul-tation with a rheumatologist or other appropriate special-ist, depending on the organs involved, is required. Exam-ples of uncontrolled disease include pleurisy, pericarditis,and/or arthritis not controlled by nonsteroidal antiinflam-matory drugs (NSAIDs); rash not controlled by topicaltherapy; active vasculitis; digital ulcers; muscle weaknessand/or elevated creatine phosphokinase (CPK) despitesteroid therapy; any CNS manifestation; and continuingevidence of active renal disease, cardiopulmonary disease,or hematologic manifestations despite therapy. The spe-cific management for such patients is best provided byspecialists, and is reviewed briefly below in the section onthe treatment of severe SLE. Persistent laboratory abnor-

malities such as hypocomplementemia or high-titer anti-DNA may also suggest underlying uncontrolled diseaseand constitute a reason for referral. When patients dem-onstrate a persistent need for dosages of medication sohigh that side effects are likely to occur, they should bereferred to an experienced consultant.

Management of disease with major organ dam-age. Patients demonstrating end-organ compromiseshould be referred to a rheumatologist or other appro-priate specialist depending on the organ(s) involved.Examples include GI involvement with motility disor-ders or ischemia, lung involvement causing shortness ofbreath, pulmonary hypertension, malignant hyperten-sion, renal insufficiency, nephrotic syndrome, severeperipheral or CNS disease (e.g., psychosis, confusion,disorientation, paresthesias, seizure, cognitive dysfunc-tion, severe unremitting headache, cerebrovascular acci-dent, transient ischemic attack, retinal vasculitis), muscleatrophy or weakness, deforming arthritis, osteoporosis(with fracture), avascular necrosis of bone, and severeskin involvement (scarring, alopecia, ulcers) (11).

Management/prevention of complications oftherapies. In some patients, the treatment is effectivebut drug toxicity or intolerance occurs. These patientsmay present with serious infections, steroid myopathy,avascular necrosis of bone, hypertension, osteoporosis,diabetes, cushingoid appearance, GI intolerance, andpersistent cytopenias (see Table 7).

Management of special clinical situations. Thereare special conditions that pose additional problems forthe SLE patient and necessitate close observation andfrequent alteration of drug regimens. Appropriate con-sultation is recommended. Some of these conditions,and reasons for close observation and consultation, areas follows: antiphospholipid antibody syndrome (manage-ment of recurrent fetal loss; venous and/or arterialthrombosis); pregnancy (assessment of disease activity,which may be confounded by the normal physiologic andimmunologic effects of the pregnancy; management ofthe gestational and postpartum treatment regimen; riskof neonatal SLE in infants of mothers with antibodies toRo/SSA and La/SSB); surgery (preoperative disease as-sessment and clearance for surgery; management of theintra- and postoperative treatment regimen [e.g., glu-cocorticoids, anticoagulants, immunosuppressive/cytotoxic agents]).

Monitoring SLE

Once a diagnosis is established and referral madefor any of the above reasons, the following guidelinesshould be followed by the managing physician(s).


Lifelong monitoring is required for most pa-tients. The cornerstone of managing SLE is lifelongpatient monitoring to detect flares of disease early andto institute prompt, appropriate therapy. In patients whohave moderate to severe disease at any time, this lifelongmonitoring may best be supervised by a physician withexperience in treatment of SLE. This is accomplished byseeing patients on a regular basis. A history-taking thatemphasizes features of SLE, appropriate physical exam-ination, and laboratory tests are required (for review,see refs. 1–8, 23, and 24) (Table 8). The frequency ofthese evaluations will depend on the activity, severity,and extent of the SLE, the response to treatment, andthe type of treatment, including the need for toxicitymonitoring. SLE disease activity can be diagnosed byspecific clinical features (e.g., arthritis, serositis, etc.) or

laboratory features (e.g., anti-dsDNA antibodies orcomplement levels), or by using a global activity index.

At routine followup visits, the following shouldbe obtained: complete blood cell count, platelet count,creatinine measurement, and urinalysis, even if thepatient has had normal values in the past. Patients withknown renal disease should have a urinalysis, 24-hoururine collection for protein, creatinine measurement,complete blood cell count, and determination of choles-terol, calcium, phosphorus, alkaline phosphatase, so-dium, and potassium levels approximately once a monthat the onset of nephritis and more often if the conditionis unstable. Measurement of 24-hour urine protein,creatinine clearance rate, or the more accurate measure-ment of glomerular filtration rate is useful to indicateresponse to therapy. In many patients, particularly those

Table 7. Recommended monitoring strategy for drugs commonly used in systemic lupus erythematosus*

DrugToxicities requiring

monitoring Baseline evaluation

Monitoring

System review Laboratory

Salicylates,nonsteroidalantiinflammatorydrugs

Gastrointestinal bleeding,hepatic toxicity, renal toxi-city, hypertension

CBC, creatinine, urinaly-sis, AST, ALT

Dark/black stool,dyspepsia,nausea/vomiting,abdominal pain,shortness ofbreath, edema

CBC yearly, creatinineyearly

Glucocorticoids Hypertension,hyperglycemia,hyperlipidemia,hypokalemia, osteo-porosis, avascularnecrosis, cataract, weightgain, infections, fluidretention

BP, bone densitometry,glucose, potassium,cholesterol,triglycerides (HDL,LDL)

Polyuria,polydipsia,edema, shortnessof breath, BP ateach visit, visualchanges, bonepain

Urinary dipstick for glucoseevery 3–6 months, totalcholesterol yearly, bonedensitometry yearly toassess osteoporosis

Hydroxychloroquine Macular damage None unless patient isover 40 years of age orhas previous eyedisease

Visual changes Funduscopic and visualfields every 6–12 months

Azathioprine Myelosuppression, hepatotoxi-city, lymphoproliferativedisorders

CBC, platelet count,creatinine, AST orALT

Symptoms ofmyelosuppression

CBC and platelet countevery 1–2 weeks withchanges in dose (every1–3 months thereafter),AST yearly, Pap test atregular intervals

Cyclophosphamide Myelosuppression,myeloproliferativedisorders, malignancy,immunosuppression,hemorrhagic cystitis,secondary infertility

CBC and differential andplatelet count, urinaly-sis

Symptoms ofmyelosuppression,hematuria,infertility

CBC and urinalysismonthly, urine cytologyand Pap test yearly forlife

Methotrexate Myelosuppression, hepaticfibrosis, cirrhosis,pulmonary infiltrates,fibrosis

CBC, chest radiographwithin past year,hepatitis B, C serologyin high-risk patients,AST, albumin,bilirubin, creatinine

Symptoms ofmyelosuppression,shortness ofbreath, nausea/vomiting, oralulcer

CBC and platelet countevery 4–8 weeks, AST orALT every 4–8 weeks,albumin every 4–8 weeks,serum creatinine, urinaly-sis

* CBC 5 complete blood cell count; AST 5 aspartate transaminase; ALT 5 alanine transaminase; BP 5 blood pressure; HDL 5 high-densitylipoprotein; LDL 5 low-density lipoprotein.


with nephritis, it is also useful to monitor serum levels ofcomplement component C3 and anti-dsDNA antibodiesat regular intervals (20,21,25–27).

Patients with longstanding SLE can develop neworgan system involvement over time (15). This is espe-cially true for renal disease in African Americans. Pa-tients with severe hemolytic anemia require a hematocritmeasurement and a reticulocyte count initially weekly.Patients with severe thrombocytopenia (,50,000/mm3)require platelet count monitoring initially weekly. Thefrequency of subsequent laboratory tests in such patientswill depend on the response to therapy.

In many SLE patients, changes in the results ofcertain laboratory tests, such as a decrease in serumcomplement levels, an increase in anti-dsDNA level, arise in erythrocyte sedimentation rate, a decrease inhemogloblin level or leukocyte or platelet counts, a risein CPK level, or the appearance of microscopic hema-turia or proteinuria, may precede a clinical disease flare.Modification of treatment at the time a change inlaboratory results is noted can significantly reduce thechance of flare (27). The clinician should establish theutility of various tests in an individual patient, thenperform those selected tests regularly to detect earlyflare. In some SLE patients, abnormalities in the resultsof such tests (particularly antibodies to dsDNA andserum complement levels) do not predict disease activa-tion (28). Monitoring of laboratory findings in patientswith SLE may be facilitated by the use of flow charts,

particularly for tracking serologic abnormalities. In ad-dition, global activity indices are useful for the assessmentof SLE disease activity in the office/clinic setting (15,23).

Finally, it is important to establish a team rela-tionship among all of the health care providers, includ-ing primary care physician, specialists, nurses, hospitalstaff, pharmacists, and the patient and family. This teamapproach will allow manifestations of disease flares ormedication toxicity to be detected at an early stage. Theteam approach would also facilitate the identification ofadditional features of the disease such as fibromyalgia(5), which may be confused with disease manifestationsbut require a different management approach than thetreatment of active disease or complications of therapy.

When should a kidney biopsy be performed?Kidney biopsy is indicated for diagnostic purposes inSLE patients in whom nephritis is suspected. Thus,patients with persistent urinary sediment abnormalitiessuch as hematuria and pyuria without adequate expla-nation (infection, menstrual period, stone), patients whohave urinary casts, or patients who have increased serumcreatinine levels should have a renal biopsy. The prog-nostic value of kidney biopsy, although controversial, hasbeen demonstrated, particularly for patients with normalserum creatinine levels (15,24,29). Patients with prolif-erative glomerular lesions and chronic changes found onkidney biopsy are at a higher risk for end-stage renaldisease and death than patients who do not demonstratethese changes. Patients with deteriorating renal func-tion, or patients not responding to conventional therapy,may need a kidney biopsy to outline a course of treat-ment (29).

Frequency of followup visits. The frequency offollowup visits is determined by the activity andseverity of the disease and its complications. Patientswith very mild stable disease may require followupvisits at 3–6-month intervals by a primary care physi-cian, internist, pediatrician, or rheumatologist. Pa-tients with more severe disease or with complicationsof therapy, as well as patients with active disease, willneed more frequent followup, as will patients duringpregnancy and postpartum periods. Patients begin-ning immunosuppressive medication will also requiremore frequent followup.

Monitoring for treatment toxicity (Tables 7 and 8).All of the medications used in SLE require vigilance toassure their safe use.

Patients taking NSAIDs should be observed forthe possibility of GI, liver, and renal toxicity. In addition,several of the NSAIDs infrequently cause aseptic men-ingitis in patients with SLE (30). Their most serious side

Table 8. Monitoring of patients with systemic lupus erythematosus

HistoryFeverWeight changeFatigueNew rashIncreased hair lossPleuritic chest painJoint pain and swelling

Physical examinationJoint swellingRash, discoid lesionsAlopeciaMucous membrane ulcersVasculitic lesionsFunduscopic examinationEdemaOther features*

InvestigationsHematologyChemistryUrinalysisSerologyRadiology

* As suggested by the history.


effects are gastritis, gastric ulceration, and GI bleeding.Patients at high risk for these complications should betreated with gastroprotective agents, of which the mosteffective may be proton pump inhibitors; H2 blockersand prostaglandin analogs are also acceptable (31).

The role of the newer cyclooxygenase 2 (COX-2)inhibitors in the management of SLE is as yet unknown.These drugs have not been tested in patients with SLE,and their effect on kidney function is unclear.

Most authorities recommend regular ophthalmo-logic assessments (every 6–12 months) to detect earlyretinal toxicity of antimalarial agents. The incidence ofthis side effect with hydroxychloroquine is low (32).

In patients receiving long-term glucocorticoidtherapy, electrolyte, glucose, and lipid levels should bemonitored to identify metabolic complications. Theyshould also undergo bone densitometry (dual x-rayabsorptiometry scanning) to identify osteoporosis and tomonitor its response to treatment (33). Patients with hip,knee, or shoulder pain suggestive of avascular necrosisof bone should undergo radiography of the appropriatesite. If radiographs are not informative, magnetic reso-nance imaging should be considered to detect avascularnecrosis at an early stage, to allow for early interventionsuch as core decompression (34). Patients taking ste-roids are compromised hosts in whom signs of infectionmay be masked. Therefore, one should always be vigilantfor infectious complications and infection with atypicalorganisms (13).

Patients receiving immunosuppressive/cytotoxicmedications (methotrexate, azathioprine, cyclo-phosphamide) should be monitored carefully for evi-dence of hematologic toxicity, liver and renal toxicity,and the possibility of infection (Table 7). At times it isdifficult to distinguish between manifestations of activeSLE and side effects of medications. While cytopeniasmay represent drug toxicity, they may also result fromactive inflammation for which drug doses should beincreased. If the cytopenias occur in association withserologic abnormalities, it is more likely that the SLE isactive than that this is a result of drug toxicity. Likewise,fever may represent active lupus or infection. If there areother clinical or laboratory manifestations of activedisease, the diagnosis is facilitated. However, since in-fection is more likely to develop in the context of activeSLE, the differentiation may become difficult (35).Patients with SLE are often treated for infection andactive disease simultaneously until the results of culturesare obtained.

Management

General considerations. All SLE patients neededucation, counseling, and support due to the complex-ity and unpredictability of the disease process. Patienteducation programs for SLE patients and their familiesare designed to provide information, knowledge, andsocial support with an emphasis on enhancing self-management skills (36). Such support may also comefrom local organizations such as the Lupus Foundationof America, Lupus Canada, and the Arthritis Founda-tion. Patients need advice regarding physical measures,including minimizing sun exposure, using sunscreens,and exercising regularly. Diet management for preven-tion of obesity, osteoporosis, and hyperlipidemia is ofparticular importance. Routine health maintenance, in-cluding regular gynecologic assessments, dental care,and ophthalmologic examinations (especially for pa-tients taking glucocorticoids or antimalarial drugs), isvery important in this chronic systemic disease. Preven-tive measures such as immunizations (e.g., hepatitis B,Haemophilus influenzae, Pneumovax, and influenza) orthe use of hormone replacement therapy should be

Table 9. Treatment of mild systemic lupus erythematosus

1. Patient educationa. Realistic expectationsb. Avoid extensive ultraviolet light exposurec. Avoid exhaustiond. Identify symptoms and signs of flaree. Comply with recommended treatmentf. Keep medical appointments

2. Analgesic treatment as needed

3. Nonsteroidal antiinflammatory drug treatment as needed(Cautions regarding side effects: gastric erosions/ulcers/bleeding,decrease in renal function, increase in liver enzyme levels, asepticmeningitis)

4. Topical glucocorticoid treatment for rash(Caution: avoid using high-potency preparations on the face formore than several days)

5. Topical sunscreens (minimum sun protection factor of 15recommended)

6. Rest when patient senses a flare beginning

7. Antimalarial drug treatment (hydroxychloroquine is mostfrequently used, at 200–400 mg/day)(Caution: patient will need ophthalmologic examination at leastannually if therapy is continued longer than 6 months)*

8. Low-dose glucocorticoid therapy (not to exceed 10 mg ofprednisone or equivalent daily)*

* Referral to specialist is recommended if these interventions arerequired.


coordinated with the SLE care expert. Since cardiovas-cular disease is a major cause of long-term morbidityand mortality among patients with SLE (13,14), strate-gies to identify and treat risk factors are essential.

Treatment of mild SLE (Table 9). Topical sun-screens. Patients with SLE may experience cutaneous orsystemic disease flares when exposed to ultraviolet light(37); these patients should be encouraged to protectthemselves from such exposure. Wearing protectiveclothing, applying sunscreens with a sun protectionfactor of at least 15 whenever outdoors, and avoidanceof sunbathing should be emphasized.

Topical glucocorticoid preparations. Creams, oint-ments, and other vehicles are used to apply glucocorti-coids to affected areas. Intermediate- rather than high-strength topical steroids should be used on steroid-sensitive areas that are prone to atrophy, such as theface. Cyclical application of more potent glucocorticoidsmay be required (38).

NSAIDs. NSAIDs are sometimes helpful for con-trol of fever, arthritis, and mild serositis. However,salicylate-induced hepatitis has been noted among pa-tients with SLE, and aseptic meningitis has developed inSLE patients given ibuprofen (31). Other NSAIDs maycause similar reactions. NSAIDs may cause or aggravatehypertension, peripheral edema, and renal impairmentin SLE patients. Whether the COX-2 inhibitors will havea better safety profile among patients with SLE remainsunknown.

Antimalarial agents (e.g., hydroxychloroquine). An-timalarial agents are useful for skin and joint manifes-tations of SLE, for preventing flares, and for otherconstitutional symptoms of the disease (32,38–40). Theymay also reduce fatigue and decrease levels of low-density lipoproteins.

Oral glucocorticoids. Patients with mild SLE usu-ally do not need systemic glucocorticoid treatment.However, some patients do not have an acceptablequality of life unless treated with low-dose daily oralternate-day glucocorticoids (#10 mg of prednisone/day or equivalent). Given the significant toxicity ofglucocorticoids, initiation of therapy with these agents,along with strategies to minimize steroid side effects(e.g., consideration of steroid-sparing agents, and pre-vention of osteoporosis and infections), is an indicationfor referral.

Treatment of serious, life-threatening, or organ-threatening SLE (Table 10). Organ involvement maylead to irreversible damage in the affected organ. Forexample, patients with lupus nephritis may developrapidly progressive renal failure. Patients with cardiac

involvement may develop heart failure, valvular insuffi-ciency, or pericardial tamponade. Severe anemia orthrombocytopenia may be life threatening. These pa-tients require care by a specialist skilled in the manage-ment of SLE.

High-dose glucocorticoids (1–8,16,24,41–43). Glu-cocorticoids are used for refractory manifestations ofSLE, as well as for severe organ-threatening disease.High-dose, daily glucocorticoid therapy (40–60 mg/dayof prednisone) improves survival among patients withsevere forms of SLE nephritis (41), but is associated withvirtually universal undesirable side effects. The dosageand mode of administration of glucocorticoids will de-pend on the nature and severity of the condition. Thus,refractory serositis may require relatively low doses, upto 20 mg per day of prednisone or equivalent. However,depending on the individual’s sensitivity to steroids, thatdosage may cause significant side effects. The treatmentof active SLE nephritis, cerebritis, or thrombocytopeniamay require high doses of 40–60 mg of prednisone perday, or intravenous pulses of up to 1 gm of methylpred-nisolone per day for 3 consecutive days. Studies ofmonthly high-dose intravenous methylprednisolone (in

Table 10. Examples of organ- or life-threatening diseasemanifestations

Cardiac PulmonaryCoronary vasculitis/

vasculopathyPulmonary hypertensionPulmonary hemorrhage

Libman-Sacks endocarditis PneumonitisMyocarditis Emboli/infarctsPericardial tamponade Shrinking lungMalignant hypertension Interstitial fibrosis

Hematologic GastrointestinalHemolytic anemia Mesenteric vasculitisNeutropenia (white blood cells

,1,000/mm3)Pancreatitis

Thrombocytopenia (,50,000/mm3)

RenalPersistent nephritis

Thrombotic thrombocytopenicpurpura

Rapidly progressiveglomerulonephritis

Thrombosis (venous orarterial)

Nephrotic syndrome

SkinNeurologic Vasculitis

Seizures Diffuse severe rash,with ulceration orblistering

ConstitutionalHigh fever (prostration)

in the absence ofinfection

Acute confusional stateComaStrokeTransverse myelopathyMononeuritis, polyneuritisOptic neuritisPsychosisDemyelinating syndrome

MuscleMyositis


addition to daily oral glucocorticoids) have shown apositive effect on severe SLE nephritis, although thetherapy is not as effective as intermittent intravenouscyclophosphamide added to oral glucocorticoids (44).The exact dosage will depend on the sensitivity of theindividual, and the exact nature of his or her disease.

Immunosuppressive/cytotoxic agents (1–9,16,24,42–48). A number of immunosuppressive/cytotoxic medi-cations have been used to treat SLE. These include aza-thioprine, cyclophosphamide, methotrexate, chlorambucil,cyclosporine, and nitrogen mustard. The choice of drug willdepend on the nature and severity of the condition, as wellas individual preference. For example, for patients withparticularly severe arthritis, methotrexate may be preferredas the first cytotoxic medication, whereas for SLE nephritis,azathioprine or cyclophosphamide may be chosen first. Ina series of long-term studies (.20 years of followup) inpatients with SLE nephritis, treatment with glucocorticoidsplus cyclophosphamide for .2 years appears to be superiorto glucocorticoids plus azathioprine, and both seem supe-rior to glucocorticoids alone in preventing renal failure inthese patients (16,24,42,43). There is evidence that cyto-toxic agents plus low-dose steroids prevent scarring in thekidney better than do glucocorticoids alone (21). However,some patients with severe disease (renal or extrarenal)respond well over both the short term and the long term toglucocorticoids alone, or they require only a few months oftreatment with cytotoxic agents plus glucocorticoids toachieve long-term improvement. Nonrenal manifestationsof SLE that may respond to cytotoxic drugs if glucocorti-coid treatment is unsuccessful or is not tolerated includecytopenia, CNS manifestations, pulmonary hemorrhage,and vasculitis (1–8,45,46). There are several reports of SLEarthritis or nephritis responding to methotrexate (47,48).Variations in responses to therapy, in addition to theconsiderable toxicity of all of the regimens, necessitateexpert management.

Management of severe SLE without renal involve-ment. Additional treatment approaches have been usedin certain circumstances among patients with SLE. In acontrolled trial, intravenous gamma globulin was notsuperior to daily high-dose glucocorticoid therapyamong patients with idiopathic thrombocytopenic pur-pura (49). However, intravenous gamma globulin canproduce short-term improvement in patients with SLE-related immune thrombocytopenia or hemolytic anemia,as can splenectomy, danazol, cyclosporine, and variouschemotherapy regimens (50–52). Plasmapheresis hasnot provided added benefit to glucocorticoids plus cyclo-phosphamide in controlled trials of SLE nephritis(53,54). However, apheresis has been used for cytope-

nias, cryoglobulinemia, and occasionally for CNS dis-ease. Plasmapheresis or plasma exchange is often life-saving in SLE-associated thrombotic thrombocytopenicpurpura (55). Cyclosporin A has been used to treatsevere disease (52); however, its low efficacy-to-toxicityratio requires that it be administered by a physician whois expert in its use. Dapsone has been used primarily forrefractory skin lesions. Retinoid derivatives have alsobeen used for resistant skin lesions (38). Patients whohave had thrombotic events in the setting of SLE usuallyrequire anticoagulation rather than immunosuppres-sion (56).

End-stage renal disease. In spite of optimal ther-apy, in some cases SLE advances to end-stage renaldisease, necessitating dialysis and/or renal transplanta-tion. The rate of recurrence of SLE in transplantedkidneys is ;6%, and rejection rates may be somewhathigher than those in the general population of patientswho have undergone renal transplantation (57). How-ever, most patients do well, and choosing this modalityrather than vigorous immunosuppressive treatmentshould be considered by both patient and physician.

Investigational treatments. Several experimentalinterventions are being studied in SLE. Some, such asDHEA, may have a steroid-sparing effect in individualswith mild disease (58). Others, such as new lymphocyte-specific immunosuppressive strategies, tolerogens, andbiologic modifiers that prevent B cell activation andautoantibody production, may be useful in the treatmentof severe SLE. All such interventions should be super-vised by specialists with experience in their use.

Summary

SLE is a complex disorder with variable presen-tations, course, and prognosis. Since its prevalence isonly 1/1,000, most primary care physicians and generalinternists will not have sufficient experience in themanagement of moderate-to-severe life-threatening dis-ease. The major tasks of the primary care physician inthe diagnosis and management of patients with SLEinclude early diagnosis, appropriate referral, monitoringpatients with mild, stable disease, and collaboration witha specialist in the management of severe disease. Guide-lines for the initial evaluation, reasons for referral, andmanagement of mild and severe SLE are provided.

ACKNOWLEDGMENTS

The Ad Hoc Committee acknowledges the contribu-tions of Dr. Suzanne Guilliam (Portland, OR), Dr. Gordon


Hardacre (Toronto, Ontario, Canada), Dr. Laura Robbins(New York, NY), and the members of the American College ofRheumatology Board of Directors for their helpful contribu-tions to the manuscript.

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