a supplement to rheumatology news · of mortality in systemic lupus erythematosus. lupus....

A SUPPLEMENT TO

Rheumatology News

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Boston UniversitySchool of Medicine

Supported by an unrestricted

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TARGET AUDIENCE: This activity has been developed for rheumatologists involved in the care of patients with systemic lupuserythematosus (SLE), including the complications of SLE such aslupus nephritis.

ACCREDITATION: This activity has been planned and implemented in accordance with the Essential Areas and Policies of theAccreditation Council for Continuing Medical Education (ACCME)through the joint sponsorship of Boston University School ofMedicine and International Medical News Group. Boston UniversitySchool of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION: Boston University School of Medicine designates this educational activity for a maximum of 1 AMA/PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

TERM OF APPROVAL: February 15, 2007–February 15, 2008

Introduction 3Robert Lafyatis, MD, Course DirectorAssociate Professor of MedicineDepartment of RheumatologyBoston University School of Medicine

Flares and Remissions: 3The Characteristic Course of SLEBevra H. Hahn, MD, ChairChief, Division of RheumatologyProfessor of MedicineUCLA David Geffen School of MedicineUniversity of California, Los Angeles

Clinical Features and Complications of SLE 6Michelle Petri, MD, MPHProfessor, Division of RheumatologyDepartment of MedicineJohns Hopkins University School of MedicineBaltimore

Managing Flares I: 8 Treatment Options for Nonrenal SLE FlaresJoan T. Merrill, MDOMRF Professor of MedicineUniversity of Oklahoma Health Sciences CenterHead, Clinical Pharmacology Research ProgramOklahoma Medical Research FoundationOklahoma City

Managing Flares II: 10 Treatment Options for Renal FlaresEllen M. Ginzler, MD, MPHProfessor of MedicineChief of RheumatologySUNY Downstate Medical CenterBrooklyn

CME Post-Test and Evaluation 12

RENAL AND NONRENAL FLARES INSYSTEMIC LUPUS ERYTHEMATOSUS:MEETING THE CLINICAL CHALLENGE

RN_Aspreva_Systemic_12-29-06 1/24/07 3:59 PM

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This supplement is based on a continuing medicaleducation symposium held November 15, 2006, inWashington, DC. It was produced by the medicaleducation department of Elsevier/InternationalMedical News Group in cooperation with BostonUniversity School of Medicine. Neither the editor ofRheumatology News, the Editorial Advisory Board,nor the reporting staff contributed to its content. Theopinions expressed in this supplement are those ofthe faculty and do not necessarily reflect the views ofthe supporter or of the Publisher.

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STATEMENT OF NEED: Systemic lupus erythematosus (SLE) is a chronic, inflammatory autoimmune disease that may affect the skin, heart, lungs, blood, kidneys, and/or musculoskele-tal system, often beginning with one organ system at the onset of the disease and possibly involving other systems as the disease progresses. Because many of the manifestations of the disease in the various organ systems may mimic the symptoms of a wide range of diseases, the diagnosis of SLE can be a clinical challenge. SLE may be mild or remittent, or in some patients, the symptoms may be severe and life-threatening.

SLE is characterized by flares and remission of disease, and treatment must effectivelyaddress the various phases: induction of remission, maintenance of remission, and managementof flares. Renal complications—lupus nephritis—develop in 50% of patients with SLE. Unlesslupus nephritis is well controlled, the disease can progress to end-stage renal disease, with theneed for dialysis and/or organ transplantation.

Clinicians must remain updated on the most recent results of ongoing research on the diagnosis of SLE and its complications, but most particularly on advances in pharmacologic therapy. This program provides practitioners with information of practical clinical use and on therapies currently in clinical trials that may result in treatment advances.

EDUCATIONAL OBJECTIVES: At the conclusion of this supplement, the participants should beable to:

• list the signs, symptoms, and clinical impact of SLE.• outline the clinical course of SLE, the importance of renal and nonrenal flares, and how

flares are defined.• state the treatment options for both nonrenal and renal flares and explain the

importance and benefits of early treatment.• describe the management of nonrenal clinical features of SLE.

FACULTY DISCLOSURES: Boston University School of Medicine asks all individuals involved in the development and presentation of Continuing Medical Education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve apparentconflicts of interest. In addition, faculty members are asked to disclose when any discussion of unapproved use of pharmaceuticals and devices occurs.

Currently, only three agents are approved by the US Food and Drug Administration for SLE.They are hydroxychloroquine, corticosteroids, and acetylsalicylic acid. Discussion of use of anyother agent is considered off-label/investigational.

Dr Lafyatis has received grant/research support from Biogen Idec, Genentech, Inc., andMillennium Pharmaceuticals, Inc. He is a consultant to Actelion Pharmaceuticals US, Inc.,Biogen Idec, Genentech, and Encysive Pharmaceuticals. Dr Ginzler has received grant/researchsupport from and is a consultant for Amgen Inc., Aspreva Pharmaceuticals Corporation, Bristol-Myers Squibb Company, Genentech, Human Genome Sciences, Inc., and TevaPharmaceutical Industries Ltd. She plans to discuss the off-label/investigational uses of a commercial product. Dr Hahn has received grant/research support from Aspreva. She is a consultant to Aspreva, Bristol-Myers Squibb, Genentech, and Teva Pharmaceutical. She plans to discuss the off-label/investigational uses of a commercial product. Dr Merrill has receivedgrant/research support from Abbott Laboratories, Amgen, Aspreva, Biogen, Bio-RadLaboratories, Inc., Bristol-Myers Squibb, DuPont, Genelabs Technologies, Inc., Genentech,Human Genome Sciences, La Jolla Pharmaceutical Company, MedImmune Inc., NabiBiopharmaceuticals, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and Otsuka America Pharmaceutical, Inc. She is a consultant to Abbott, Biogen Idec, Bio-Rad,Bristol-Myers Squibb, Dynavax Technologies Corporation, Eisai Co., Ltd., Genelabs, Genentech, Human Genome Sciences, Immunomedics, Inc., La Jolla, the Lupus Foundation of America, Medarex, Inc., MedImmune, Otsuka, Teva, and Wyeth. She is on the speakersbureau for Bristol-Myers Squibb and Genentech. Dr Merrill plans to discuss the off-label/investigational uses of a commercial product. Dr Petri has received grant/research support from Bristol-Myers Squibb, Immunomedics, MedImmune, and Teva and is a consultant toGenelabs, Genentech, and MedImmune. She does not plan to discuss off-label/investigational uses of a commercial product.

PLANNING COMMITTEE: Jenny R. McMahon and Sylvia H. Reitman of Rheumatology News and Julie White of Boston University School of Medicine have nothing to disclose regarding conflicts of interest.

RENAL AND NONRENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS: MEETING THE CLINICAL CHALLENGE


RENAL AND NONRENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS 3

efying the scrutiny of laboratory and clinical investigators, systemiclupus erythematosus (SLE) contin-

ues to challenge clinicians and their patients, who number 1.5 million in theUnited States.1 The precise cause ofthe disease remains unknown, althoughresearch has clearly shown that anautoimmune cascade generates wavesof autoantibodies that can induce organ-destroying inflammation at multiple sites inthe body.

In the absence of a cure, better patient care has led to improved SLE survival. Since the 1980s, 5-year survivalfor SLE has increased beyond 90%.2

However, as patients live longer, diseasemorbidity and treatment-related complica-tions are encountered with increasing frequency. Whereas disease flares andinfections are significant contributors tomortality early in the course of the disease, coronary artery disease hasemerged as a leading cause of death inpatients with long-standing SLE.3

Long-term follow-up of patients withSLE has revealed several distinct diseasepatterns. True remission is rare, but some

patients do have long periods of quies-cence. The most common SLE patternsare relapsing/remitting and chronicactivity.4 The ability to prevent targetorgan damage plays a major role in theclinical course and outcome of SLE.5

Clinicians who care for patients withSLE continue to be hampered by a lack of specific therapies. Currently, only three drugs are approved for treatment ofSLE: hydroxychloroquine, corticosteroids,and acetylsalicylic acid. Since landmarkstudies showing its efficacy, cyclophos-phamide has become the standard ofcare for lupus nephritis and also usedfor other severe disease manifestations.Recently, however, mycophenolate mofetildemonstrated superior activity and amore favorable side-effect profile ina randomized comparison againstcyclophosphamide.6

Other agents being evaluated as potential SLE therapies include rituximab,leflunamide, and abatacept. Investigationalcompounds in various stages of clinicalevaluation for SLE include belimumab,epratuzumab, and edratide. The rapidprogress in investigating new therapeu-

tics—targeting different aspects of theimmune system—will hopefully lead tonew treatments of SLE in the near future.

Recently, a panel of experts in themanagement of SLE discussed the current status of the disease and its treatment options. Their presentations and observations are summarized in thefollowing supplement to RheumatologyNews. Readers will f ind the articlestimely, informative, and readily applicableto the care of patients with SLE.

References1. Lupus Foundation of America. About lupus: Introduction

to lupus. Available at: http://www.lupus.org. AccessedJanuary 9, 2007.

2. Gladman DD, Urowitz MB. Morbidity in systemic lupus erythematosus. J Rheumatol. 1987;14(suppl 13):223-226.

3. Uramoto KM, Michet CJ Jr, Thumboo J, et al. Trends in theincidence and mortality of systemic lupus erythematosus,1950-1992. Arthritis Rheum. 1999;42:46-50.

4. Barr SG, Zonana-Nacach A, Magder L, Petri M. Patterns ofdisease activity in systemic lupus erythematosus. ArthritisRheum. 1999;42:2682-2688.

5. Rahman P, Gladman DD, Urowitz MB, et al. Early damage as measured by the SLICC/ACR damage index is a predictorof mortality in systemic lupus erythematosus. Lupus.2001;10:93-96.

6. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolatemofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353:2219-2228.

he onset of clinical systemic lupuserythematosus (SLE) may be abruptand occur over a period of a few

weeks, or it may take years to evolve. Thecondition has its genesis in genetic suscep-tibility, and the number of genes and genet-ic alterations identified as predisposingcontinues to increase. For reasons that haveyet to be fully explained, SLE has a pro-nounced female predominance. Variousenvironmental factors contribute to emer-gence of SLE, including ultraviolet lightand infection with Epstein-Barr virus. Anabnormal immune response, characterizedby SLE autoantibodies, precedes the onset ofsymptomatic SLE, usually by about 3 years.

The emergence of clinical disease inpatients with SLE is associated withinflammation, complement activation, therelease of cytokines and chemokines, andactivation of proteolytic enzymes.Symptomatic expression of SLE leads toacute and chronic inflammation and chron-ic oxidative damage that can affect multipleorgan systems.

The various predisposing factors

involved in the evolution of SLE suggestopportunities to intervene and prevent theemergence of clinical disease. Key stagesin the disease process exhibit a dichoto-mous path of progression. For example,some patients with SLE autoantibodiesdevelop clinical disease and others do not.Some patients with clinical disease havetarget organ damage and others do not.This dichotomy in disease expressionshould guide the development of strategiesto arrest the disease process.

Recent Epidemiologic TrendsOne notable trend in SLE epidemiologyhas been improved survival, which hasbeen documented in multiple, recentlypublished studies from the United States,Canada, Europe, and Japan (Figure onpage 4).1-6 Throughout the developed world,the 10-year survival among patients withSLE exceeds 90%, and 30-year survival isapproximately 70%. Both figures representdramatic improvement compared to 20years ago. Deaths from renal disease andinfection are declining, although athero-

sclerosis—a major principal cause of deathin patients with SLE after the first decadeof disease—is increasing. In addition, thepresence of lupus nephritis continues tohave an adverse impact on survival.7

Factors that predict a poor prognosisin SLE—that is, 10-year mortality ofapproximately 50%—have been welldefined (Table on page 5). These includeproliferative forms of nephritis; failure ofserum creatinine levels and proteinuria toimprove after 6 months of treatment;severe SLE, defined by SLE DiseaseActivity Index (SLEDAI) score >10 andmajor-organ involvement; hemolytic ane-mia; low serum complement; the presenceof antiphospholipid antibodies; vasculardisease; African American or Hispanic/Texas ethnicity; and poverty.1,5,8-10

Classification Criteria for Renal BiopsyRenal biopsy is recommended in allpatients with nephritis if the risk is accept-able. Physicians who request renal biopsiesshould expect pathologists and nephrolo-gists to follow the most recent update of

TFLARES AND REMISSIONS: THE CHARACTERISTIC COURSE OF SLE

Bevra H. Hahn, MD, Chair

DINTRODUCTION

Robert Lafyatis, MD, Course Director


the renal biopsy histologic classificationcriteria developed by the InternationalSociety of Nephrology and the RenalPathology Society.11 However, the criteriado not address the status of the renaltubules or blood vessels; comments aboutthese aspects of the biopsy should beincluded in the pathology report becauseloss of tubules and extensive vascular dam-age predict a worse prognosis and haveimplications for therapy.

Evaluating New TherapiesSeveral possible therapies for SLE haveentered clinical evaluation within the past 5to 10 years. Some agents that demonstratedpromise nonetheless failed to secure licens-ing approval. These unsuccessful ventureshave revealed aspects of the clinical evalu-ation process that could be improved.Criticism of SLE clinical trials includes theassertion that current American College ofRheumatology (ACR) diagnostic criteriafor SLE are inadequate. For example,development of peripheral neuropathyclearly results from the autoimmune dis-ease but is not a criterion for diagnosis ofSLE and, thus, might not be sufficient toenroll a patient in a clinical trial.

A second challenge in the clinicalevaluation of new therapies for SLE relatesto imperfect patient populations. As anexample, patients screened for enrollmentin a trial might be seronegative for anti-nuclear antibodies. Not uncommonly inclinical practice, patients with active SLEno longer have autoantibodies that arediagnostic for SLE. Such heterogeneityposes a dilemma when investigators are consid-ering patients for enrollment in clinical trials.

In addition, data from clinical studiesdemonstrate a lack of class I evidence fromprospective, double-blind, randomized tri-als that meet the proposed primary out-

come. However, it is my opinion that cur-rent criteria for diagnosis, disease activity,and damage are adequate to identify highlyeffective therapies in a properly designedprospective controlled trial.

The ACR recently developed criteriato evaluate the quality of evidence in clinical studies for lupus nephritis.12

According to the ACR, an effective therapyshould demonstrate evidence of a benefi-cial effect on renal function, protein, andurine sediment, as well as evidence ofdurability of these effects.

In evaluating therapy for SLE pa-tients with active disease, cliniciansshould focus on three issues: (1) whethertherapy induces acceptable improvement (remission, if possible), (2) whether itmaintains improvement, and (3) whether it prevents organ damage.

Current TherapiesCYCLOPHOSPHAMIDE. Cyclophosphamideremains an effective treatment option forSLE. A meta-analysis of clinical trialsinvolving patients with lupus nephritisshowed that intravenous (IV) cyclophos-phamide reduced mortality by 20% and therisk of end-stage renal disease by 16%compared to prednisone.13 Moreover, thenumber needed to treat with an immuno-suppressant plus prednisone to prevent onedeath was 7.6, making that combinationhighly cost-effective.

Despite its effectiveness, cyclophos-phamide’s toxicity potential often leads to side effects that many patients cannottolerate. Alternative formulations and treat-ment schedules have been examined withmixed results. Daily oral therapy hasproven to be no safer or more effective than monthly IV administration. Limitedevidence suggests that administration ofcyclophosphamide at lower doses over

shorter time intervals might be better tolerated, with no loss of eff icacy. Starting patients on cyclophosphamide and then transitioning them to a less toxic immunosuppressant after 6 months is anoption that is currently being explored.Finally, clinical experience with mycophe-nolate mofetil (MMF) suggests that it maybe better and safer than cyclophosphamideboth to induce or to maintain improvementin lupus nephritis.14

AZATHIOPRINE. For some time, azathio-prine has been viewed as less potent than cyclophosphamide for treatment of lupus nephritis; however, a recent publication might have reopened thedebate. A group of Dutch investigators15

reported that azathioprine plus pulsedmethylprednisolone and oral prednisoneled to at least as many complete and partial remissions as did cyclophos-phamide and oral prednisone. However,after a median follow-up of 5.7 years, more patients on azathioprine had a doubling of serum creatinine; fewerremained relapse-free and/or avoided thecombined end point of end-stage renal disease, relapse, and death. Azathioprinewas not as good as cyclophosphamide formaintaining remission.

In another study involving patientswith lupus nephritis,16 investigatorscompared MMF, cyclophosphamide,and azathioprine as maintenance therapyafter cyclophosphamide induction therapy.All patients received seven monthly IVbolus doses of cyclophosphamide plus corticosteroids and then were randomizedto maintenance therapy with quarterly IVcyclophosphamide, daily oral MMF, ordaily oral azathioprine for 1 to 3 years. The results showed that MMF was signifi-cantly better than IV cyclophosphamide,that azathioprine had a small, but non-significant, advantage over IV cyclophos-phamide, and that MMF and azathioprinedemonstrated similar efficacy for main-taining improvement.

MYCOPHENOLATE MOFETIL. Oral MMFdemonstrated a signif icant advantageover IV cyclophosphamide in inducingimprovement in patients wtih activelupus nephritis in a recent randomized,controlled clinical trial.14 The results of thattrial are discussed in Dr Ginzler’s article onpage 10 of this supplement.

CURRENT THERAPIES IN SUMMARY. Manyclinicians today have adopted a standard ofcare of induction therapy with daily MMFplus corticosteroids, or monthly IVcyclophosphamide plus corticosteroids,until clinical response or 6 months; thisshould be followed by maintenance therapy

4 RENAL AND NONRENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS

1009080706050403020100

5 10 15 20 30

Perc

ent S

urvi

val R

ate

YearInternational, USA, Canada, Europe, and Japan.

Figure. Survival in SLE 20061-6



from the Euro-Lupus and the LUMINA projects. Lupus.2006;15:1-2.

7. Cervera R, Khamashta MA, Font J, et al. Morbidity and mor-tality in systemic lupus erythematosus during a 10-yearperiod: A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine. 2003;82:299-308.

8. Houssiau FA, Vasconcelos C, D’Cruz D, et al. Early responseto immunosuppressive therapy predicts good renal out-come in lupus nephritis: Lessons from long-term follow-up of patients in the Euro-Lupus Nephritis Trial.Arthritis Rheum. 2004;50:3934-3940.

9. Alarcon GS, McGwin G Jr, Petri M, et al. Time to renal disease and end-stage renal disease in PROFILE: A multiethnic lupus cohort. PLoS Med. 2006;3:e396.

10. Cook RJ, Gladman DD, Pericak D, Urowitz MB. Prediction of short term mortality in systemic lupus with time dependent measures of disease activity. J Rheumatol. 2000;27:1892-1895.

11. Weening J, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol.2004;15:241-250.

12. Ruperto N, Ravelli A, Oliveira S, et al. The PediatricInternational Trials Organization/American College ofRheumatology provisional criteria for the evaluation ofresponse to therapy in juvenile systemic lupus erythematosus:Prospective validation of the definition of improvement.Arthritis Rheum. 2006;55:355-363.

13. Bansal VK, Beto JA. Treatment of lupus nephritis: A meta-analysis of clinical trials. Am J Kidney Dis.1997;29:193-199.

14. Ginzler E, Dooley MA, Aranow C, et al. Mycophenolatemofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353:2219-2228.

15. Grootscholten C, Ligtenberg G, Hagen EC, et al.Azathioprine/methylprednisolone versus cyclophos-phamide in proliferative lupus nephritis. A randomized,controlled trial. Kidney Int. 2006;70:732-742.

16. Contreras G, Pardo V, Leclerq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med.2004;350:971-980.

17. Somers EC, Marder W, Christman GM, et al. Use of agonadotropin-releasing hormone for protection againstpremature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum.2005;52:2761-2767.

18. Fessler BJ, Alarcon GS, McGwin G Jr, et al. Systemic lupuserythematosus in three ethnic groups: XVI. Association of hydrochloroquine use with reduced risk of damageaccrual. Arthritis Rheum. 2005;52:1473-1480.

19. de Nijs RN, Jacobs JW, Lems WF, et al. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med. 2006;355:675-684.

with daily MMF, daily azathioprine, or pos-sibly quarterly cyclophosphamide.

Proteinuria with or without hyperten-sion should be treated with an angiotensin-converting enzyme (ACE) inhibitor or thecombination of an ACE inhibitor and anangiotensin-receptor blocker (ARB).

Prevention of Organ DamagePreventing organ damage attributable toSLE or its therapy is now possible, atleast for some organ systems. Cyclo-phosphamide-induced damage to theovaries can be prevented by administeringthe gonadotropin-releasing hormone ana-log leuprolide, 3.75 mg once a month, 10 to14 days before each IV dose of cyclophos-phamide. A recent nonrandomized study ofleuprolide treatment compared to noleuprolide demonstrated ovarian preserva-tion of nearly 100% in women who optedfor leuprolide treatment.17

Treatment with hydroxychloroquineoffers the potential for significant,although incomplete, protection againstorgan damage. Findings from a largeprospective cohort study18 showed treat-ment with hydroxychloroquine remainedprotective against damage accrual inpatients with SLE who had no evidence oforgan damage at baseline.

As previously stated, prevention ofrenal damage in patients with proteinuria ismore likely in those who have good bloodpressure control and those who are treatedwith an ACE inhibitor or an ACE inhibitorplus an ARB, whether or not they arehypertensive.

Morbidity and mortality attributableto atherosclerosis continue to increase inpatients with SLE. Multiple cardiovascular therapies can help reduce atheroscleroticrisk in SLE; these include antihyperten-sives, ACE inhibitors and ARBs, statinlipid-lowering drugs, and aspirin and antimalarials to reduce clotting potential.In addition, suppression of SLE diseaseactivity affords further protection againstatherosclerosis and its complications.

INFECTION PREVENTION. Infection of anytype can pose a serious threat to the patientwith SLE. An effective prevention strategyshould incorporate immunization and suppression therapies. All patients arepotential candidates for immunizationagainst influenzavirus and Pneumococcus,and human papillomavirus. Splenectomizedpatients also should consider immunizationagainst Meningococcus.

Patients with the following conditionsshould receive certain types of preventivetherapy: Pneumocystis carinii pneumoniain highly immunosuppressed patients,recurrent urinary tract infections, andrecurrent oral/genital herpes infections.

Prevention of OsteoporosisChronic treatment with glucocorticoidscan predispose patients to osteoporosis.Bisphosphonate therapy has demonstratedsuperiority over vitamin D plus calcium for maintaining bone mass and reducingfracture risk in patients on glucocorticoidtherapy.19

SummaryMortality associated with SLE hasdeclined substantially over the past 20years, including most of the prominentcauses of death. The current standard ofcare for patients with SLE should focus onachieving three principal therapeutic goals:(1) induction of acceptable improvementand remission if possible; (2) maintenanceof the improvement; and (3) prevention of organ damage. IV cyclophosphamideremains an accepted standard of care forpatients with lupus nephritis, althoughrecent studies suggest that mycophenolatemofetil might be superior with respect to efficacy and tolerability. Patients withSLE also should receive appropriate treatment to prevent organ damage, athero-sclerosis, infection, and steroid-inducedosteoporosis.

References1. Bernatsky S, Boivin JF, Joseph L, et al. Mortality in

systemic lupus erythematosus. Arthritis Rheum.2006;54:2550-2557.

2. Doria A, Iaccarino L, Ghirardello A, et al. Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med. 2006;119:700-706.

3. Funauchi M, Shimadzu H, Tamaki C, et al. Survival study by organ disorders in 306 Japanese patients with systemic lupus erythematosus: Results from a single center. Rheumatol Int. 2007;27:243-249.

4. Chan TM. Determinants of patient survival in systemic lupuserythematosus—focusing on lupus nephritis. Ethn Dis.2006;16(2 suppl 2):S2-66-9.

5. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine.2006;85:147-156.

6. Cervera R, Khamashta MA. Epidemiology of systemic lupuserythematosus at the change of the millennium: Lessons

Table. Indicators of Poor Prognosis in SLE 1,5,8-10

Cr=creatinine; SLEDAI=systemic lupus erythematosus Disease Activity Index.

� Proliferative forms of nephritis� Serum Cr >1.4 mg/dL� Urinary protein > 2.6 g� Chronic change on biopsy

� Failure of Cr and urinary protein to improve at 6 months of Rx

� Severe disease: high activity (SLEDAI >10), major organs involved

� Hemolytic anemia

� Low serum complement 3

� Antiphospholipid antibodies

� Vascular disease

� African American or Hispanic/Texanethnicity

� Poverty



dvances in laboratory and clinicalresearch have helped solve some of the mysteries surrounding systemic

lupus erythematosus (SLE), but knowledgeabout many aspects of the conditionremains incomplete. For example, clini-cians now have at their disposal a variety of objective information to guide theirrecognition of lupus flares. Yet, the overallstatus of flare recognition might be likenedto the age-old subjective definition appliedto objectionable literature or art: I know itwhen I see it. Similarly, a number of clues have emerged to aid in identifyingpatients who are more likely to have disease flares, but flares remain difficult topredict. At least two aspects of SLE havebecome quite clear: (1) true remissionrarely occurs and (2) organ system damagefrequently occurs. This mix of imprecisionand certainty challenges physicians tocombine the sciences of medicine and theart of medicine to provide the best carepossible for patients with SLE.

Nonrenal SLE FlaresThree distinct patterns of disease activityhave been identified in patients with SLE:flare (relapsing/remitting), chronic activity,and long quiescence.1 Between 40% and50% of patients with SLE fall into the re-lapsing/remitting category, which is char-acterized by spikes in disease activity fol-lowed by obvious declines in activity. Thepattern has been demonstrated with multi-ple types of disease activity indices. In theJohns Hopkins SLE patient population, theincidence of flare is 0.65 per patient-year, andthe median time to flare is 12 months.2

Equally prevalent is a pattern we havecharacterized as “chronic activity.”1 In theJohns Hopkins experience, about half ofpatients with lupus have some degree ofdisease activity on an ongoing basis. Thephysician might tolerate some types ofchronic activity because some of our cur-rent treatments, such as prednisone, are tootoxic to use in high doses.

FLARE CHARACTERISTICS. Multiple recentstudies have identif ied a variety of environmental triggers of SLE itself and of SLE flares. Documented triggersinclude exposure to ultraviolet light, certain drugs (including echinacea and granulocyte colony-stimulating factor), smoking, and infections/antibiotic therapy. Unfortunately, these triggers donot uniformly induce SLE flares, so physicians are left to tell their patients that flares are unpredictable.

Flares, both nonrenal and renal, can be prevented with hydroxychloroquine prophylaxis.3,4 Every patient with lupusshould receive hydroxychloroquine andcontinue to receive it even after an episode of lupus nephritis has been controlled; continuing the drug can double the rate of complete response with mycophenolate mofetil therapy.4

Flares can involve multiple organ systems.The most common sites of involvement are cutaneous and musculoskeletal.2 Thisobservation emphasizes that current treat-ment of SLE still routinely involves the useof older drugs such as hydroxychloroquineto address cutaneous and musculoskeletalmanifestations that do not require immuno-suppression.

The utility of serologic tests in themanagement of SLE has been contro-versial. Certainly, the presence of anti-dsDNA or low serum complement levels is very useful in helping make the diagnosis of SLE. However, anti-dsDNAantibody levels actually decline on the day that a patient presents with a flare.5

The levels likely decline because the anti-dsDNA forms immune complexes thatare deposited in organs.

At Johns Hopkins, we have evaluatedthe impact of demographic and serologicfactors on the predictive ability of theBritish Isles Lupus Assessment Group(BILAG) index of SLE disease activity. Weidentified several factors that can be usefulin predicting a patient’s risk of flare during

the next year. Statistically significant prog-nostic factors were African American ethnicity, low levels of complement 3 andcomplement 4, and anti-dsDNA positivity(Table 1).5,6 In our experience, the presenceof these factors doubles the likelihood thata patient will have a flare during the next12 months.

LONG QUIESCENCE/REMISSION. Long qui-escence is the pattern that all clinicianswish for their patients with SLE. Patientsin long quiescence have prolonged periodswithout detectable disease activity. Theterm “remission” probably should not be used, because disease activity mayeventually return. We recently developed a definition of remission that is based on three criteria: no clinical or laboratorydisease activity for 2 years, no use of prednisone, and no use of immuno-suppressive agents.7 By this definition, we found that only 3.4% of ourpatients with SLE at Johns Hopkinsachieved remission.7

Organ DamageAvoidance of permanent organ damage isthe key to long-term survival in SLE. Data from a Toronto SLE cohortdemonstrated a 10-year survival of 93% in patients who had no organ damage atinitial presentation compared to 75% inpatients who had early organ damage bythe Systemic Lupus InternationalCollaborating Clinics/American College of Rheumatology index (P=0.0002).8

In the Johns Hopkins cohort,9 half the patients have accrued organ damage,headed by a 25.2% incidence of muscu-loskeletal injury. Obviously, some types of damage, such as cardiovascular andrenal, have greater implications for sur-vival. In our cohort, 10% of patients havecardiovascular damage and almost 12%have renal damage (Table 2).

The use of corticosteroids contributesto much of the organ damage accrued by patients with SLE. The Toronto groupfound that 75% of organ damage at 15years could be attributed directly or indi-rectly to corticosteroid use.10 Moreover, the route of administration and dosing ofcorticosteroids influence the risk for andtype of organ damage a patient may develop. For example, higher prednisonedoses increase the risk of cataract, stroke, venous thrombosis, avascularnecrosis, and hypertension. Cumulativeprednisone exposure of a patient with SLEinfluences the risk of cataract, coronary

A

Factor at Baseline No A or 2B Later A or 2B P-value OR (95% CI)

African American 35% 49% 0.0397 1.77 (1.04, 3.01)

Low complement 3 18% 36% 0.0019 2.57 (1.45, 4.55)

Low complement 4 17% 36% 0.0009 2.75 (1.54, 4.90)

Anti-dsDNA positive 21% 37% 0.0070 2.24 (1.28, 3.92)

Table 1. Influence of Demographic and Serologic Factors in BILAG Flare5,6

CLINICAL FEATURES AND COMPLICATIONS OF SLE

Michelle Petri, MD, MPH

BILAG= British Isles Lupus Assessment Group; CI=confidence interval; OR=odds ratio.


artery disease, and osteoporosis. Use ofintravenous methylprednisolone increasesthe risk of only one type of damage: cogni-tive impairment.11 This may actually reflecta “bias of indication,” because cortico-steroids are frequently used to treat centralnervous system lupus flares.

COGNITIVE IMPAIRMENT. Cognitive impair-ment has emerged as a major form of organdamage in patients with SLE. As many as80% of all patients with lupus have somedegree of impairment in cognitive func-tion.12 The underlying mechanisms of cog-nitive impairment have yet to be deter-mined, but studies in mice have implicatedantibodies to N-methyl-D-aspartate recep-tor, raising the possibility that treatmenttargeting this might minimize or preventcognitive impairment.13 In humans, the fac-tors associated with cognitive impairmentseem to differ at the time of diagnosis com-pared to later in the clinical course.Depression appears to be associated inearly lupus,14 whereas persistent positiveantiphospholipid antibodies are associatedwith cognitive impairment further along indisease progression.15, 16

CARDIOVASCULAR DISEASE. Cardiovas-cular disease is the major cause of death in patients with SLE. A comparison of 498 women with SLE and 2,208 women inthe Framingham Offspring Study showedthat the SLE patients from 35 to 44 years of age had a 50-fold greater risk of myocardial infarction (MI) than that ofthe Framingham women in the same agerange. Factors associated with MI wereolder age at SLE diagnosis, longer lupusdisease duration, longer duration of corti-costeroid use, hypercholesterolemia, andpostmenopausal status.17 In the JohnsHopkins SLE cohort, we have found thatpredictors of coronary artery diseaseinclude older age, higher homocysteinelevels, hypertension, diabetes mellitus,renal insufficiency, and lupus anticoagulant.

Even after adjustment for convention-al cardiovascular risk factors, patients withSLE have an increased risk for atheroscle-rosis. Using Framingham logistic regres-sion equations, Canadian researchersshowed that patients with SLE have a relative risk of 8.3 for MI, 6.7 for cerebrovascular accident, and 5.7 for anycardiovascular event.18

Carotid plaque formation is a meansof evaluating subclinical atherosclerosis. In a study comparing patients with andwithout SLE, those with SLE had significantly greater carotid plaque. Inpatients with SLE, carotid plaque wasassociated with older age and longer dis-ease duration. Patients with SLE who had more plaque accumulation were less likely

to have autoantibodies and had less expo-sure to prednisone and immunosuppressiveagents.19

MALIGNANCY. Recent studies have shownthat malignancy is yet another health threatassociated with SLE. In particular, patients with SLE tend to have a higherincidence of lymphoma and to developaggressive forms of lymphoma.20, 21 Patientswith SLE have an increased risk for all cancers combined, for all hematologicmalignancies, for lung cancer, and forhepatobiliary cancer.22

SummaryFlares are a common feature of SLE inmany patients. Flares occur more often inAfrican Americans and in patients who have serologically active disease.Remission is rare. Organ damage is common, and use of corticosteroids to treat SLE plays a major role in theinduction of damage. Most patients havesome degree of cognitive impairment,which may be autoantibody mediated.Atherosclerosis is a common form of damage associated with SLE and is related to both traditional cardiovascularrisk factors and to lupus-specific factors.Patients with SLE have an increased risk of malignancy, particularly aggressiveforms of lymphoma.

References1. Barr SG, Zonana-Nacach A, Magder L, Petri M. Patterns

of disease activity in systemic lupus erythematosus.Arthritis Rheum. 1999;42:2682-2688.

2. Petri M, Genovese M, Engle E, Hochberg M. Definition,incidence, and clinical description of flare in systemiclupus erythematosus. A prospective cohort study. Arthritis Rheum. 1991;34:937-944.

3. Canadian Hydroxychloroquine Study Group. A randomizedstudy of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med.1991;324:150-154.

4. Kasitanon N, Fine DM, Haas M, et al. Hydroxychloroquineuse predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus.2006;15:366-370.

5. Ho A, Magder LS, Barr SG, Petri M. Decreases in anti-double stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44:2342-2349.

6. Ho A, Barr SG, Magder LS, Petri M. A decrease in comple-ment is associated with increased renal and hematologicactivity in patients with systemic lupus erythematosus.Arthritis Rheum. 2001;44:2350-2357.

7. Petri M, Link K. Prevalence and predictors of remission inSLE [abstract]. Arthritis Rheum. 2006;54(9 suppl):S443.

8. Rahman P, Gladman DD, Urowitz MB, et al. Early damage as measured by the SLICC/ACR damage index is a predictorof mortality in systemic lupus erythematosus. Lupus.2001;10:93-96

9. Petri M, Barr SG, Zonana-Nach A, Madger L. Measures of disease activity, damage, and health status. The Hopkins Lupus Cohort Experience. J Rheumatol.1999;26:502-503.

10. Gladman DD, Urowitz MB, Rahman P, et al. Accrual of organ damage over time in patients with systemic lupuserythematosus. J Rheumatol. 2003;30:1955-1959.

11. Zonana-Nacach A, Barr SG, Magder LS, Petri M. Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum.2000;43:1801-1808.

12. McLaurin EY, Holliday SL, Williams P, Brey RL. Predictors of cognitive dysfunction in patients with systemic lupus erythematosus. Neurology. 2005;64:297-303.

13. DiGiorgio LA, Konstantinov N, Lee SC, et al. A subset of lupus anti-DNA antibodies cross-reacts with the N2 glutamate receptor in systemic lupus erythematosus. Nat Med. 2001;7:1189-1193.

14. Naqibuddin M, Wallace DJ, Weisman MH, et al. Depression is associated with poorer cognitive function in newly diagnosed SLE patients [abstract]. ArthritisRheum. 2005;52(9 suppl):S379.

15. Hanly JG, Walsh NM, Fisk JD, et al. Cognitive impairment and autoantibodies in systemic lupus erythematosus. Br J Rheumatol. 1993;32:291-296.

16. Menon S, Jameson-Shortall E, Newman SP, et al. A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus. Arthritis Rheum. 1999;42:735-741.

17. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: Comparisonwith the Framingham Study. Am J Epidemiol.1997;145:408-415.

18. Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 2001;44:2331-2337.

19. Roman MJ, Shanker BA, Davis A, et al. Prevalence andcorrelates of atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349:2399-2406.

20. Bernatsky S, Ramsey-Goldman R, Clarke AE. Revisiting theissue of malignancy risk in systemic lupus erythematosus.Curr Rheumatol Rep. 2005;7:467-481.

21. Bernatsky S, Ramsey-Goldman R, Rajan R, et al. Non-Hodgkin’s lymphoma in systemic lupus erythematosus. Ann Rheum Dis. 2005;64:1507-1509.

22. Bernatsky S, Boivin JF, Joseph L, et al. An internationalcohort study of cancer in systemic lupus erythematosus.Arthritis Rheum. 2005;52:1481-1490.


25.2% Musculoskeletal15.0% Neuropsychiatric12.6% Ocular11.7% Renal10.4% Pulmonary10.1% Cardiovascular

7.4% Gastrointestinal7.4% Skin5.5% Peripheral vascular6.1% Diabetes mellitus2.5% Malignancy1.2% Premature gonadal failure

Table 2. Fifty Percent of Patients With SLEHave Organ Damage9


ystemic lupus erythematosus (SLE)has a complicated, variable, andunpredictable symptom complex.

Pathology may vary between patients, even when they exhibit the same organinvolvement. This heterogeneity may bea natural consequence of immune com-plexity involving myriad potential geneticvariations in hundreds of interactingproteins. SLE could represent inevitableconsequences of immune versatility linkedto species survival, analogous to a badhand in a game of poker. The heterogeneitythat characterizes SLE does not reflect adisordered immune response, but rather animbalance; therefore, treatment should aimto restore balance, not suppress immunity.

Available TherapiesFew therapies are approved for SLE:hydroxychloroquine, corticosteroids, andacetylsalicylic acid—other agents in use are not approved for SLE. However, in considering the various SLE treatmentoptions, several are available that are reasonably safe and effective, as judged by current standards. Antimalarial therapywith hydroxychloroquine or chloroquine is the most widely used treatment for mild SLE, although corticosteroids anddehydroepiandrosterone (DHEA) are alsohelpful in some patients. For patients with moderately severe lupus symptoms, a variety of approved and unapprovedtherapies exist, including cortico-steroids, DHEA, dapsone, thalidomide,azathioprine, methotrexate, leflunomide,mycophenolate mofetil (MMF), andcyclophosphamide. Severe lupus canbe treated with intravenous immuno-globulin/plasma exhange as well as thedrugs used for moderate disease, withthe exception of DHEA (Table 1).1,2

Azathioprine, leflunomide, metho-trexate, and MMF are moderate-intensitytherapies that are widely used in the treat-ment of SLE. Although these drugs maybe considered broadly immunosuppres-sive, each one, in fact, targets B cells tosome degree.3 Azathioprine, methotrex-ate, MMF, and leflunomide all haveantiproliferative effects and influence mat-uration signals and glycosylation of sur-face proteins on various immune cells.MMF has a fivefold greater affinity for thetype 2 isoform of the inosine monophos-phate dehydrogenase enzyme that is selec-tively expressed in activated lympho-cytes. This affinity might result in morepotent cytostatic effects on lymphocytesthan other cell types.4-6

Do these widely used agents differ in their clinical activity? Methotrexate has been evaluated in patients with lupus in two randomized clinical trials.7,8

The evidence suggests that the drug ishelpful in the management of cutaneousand musculoskeletal manifestations oflupus and that it might be steroid sparing.There is no evidence to indicate thatmethotrexate has any effect on lupusnephritis.

Azathioprine has been evaluated inmultiple randomized trials of patients with lupus nephritis but not in patients with nonrenal SLE.1 Consequently, littleevidence-based literature exists to supportthe clinical use of azathioprine in this population, although rheumatologists fre-quently use this medication to treat patientswith SLE.

MMF has been evaluated in several randomized trials of SLE patients withnephritis.9-11 Case reports indicating MMF’spotential efficacy for treating other mani-festations of SLE suggest that this agentmay have a broad spectrum of activity.

One recent study suggests that opportunities exist in making SLE pharma-cotherapy more effective.12 In this study,cohorts of patients with nonrenal SLE weretreated with increasing doses of azathio-prine, ranging as high as 3.5 to 4 mg/kg.Assays have now become commerciallyavailable to measure the metabolites of6-mercaptopurine, and this was done in thestudy to determine if dose-limiting toxicity

could be defined with these measures. Theresults showed that 6 of 10 patients treatedwith a dose of 3.5 mg/kg had clinicalresponses, as did both patients who received4 mg/kg. The optimal response rate withdoses up to 3 mg/kg was 31.5%. Althoughmany rheumatologists use this treatmentbased on good overall clinical experiences,this study suggests that optimal responserates are only achieved at doses that manypatients will not be able to tolerate.

Clinical TrialsSeveral prospective clinical trials haveevaluated therapies in patients with non-renal mild or moderate SLE. One of themost recent compared the antimetaboliteclofazamine and chloroquine in 33 patientswith cutaneous SLE.13 The results demon-strated equivalent effects on the skin, butthe chloroquine group had fewer flares. Animportant conclusion that can be drawnfrom this study is that hydroxychloroquineand chloroquine are quite effective for SLEskin disease, and physicians should nothesitate to try higher doses of the drugsbefore turning to other, potentially moredangerous medications, particularly forlong-term therapy.

Other studies have demonstrated variable results with agents such asleflunomide, IDEC 131 (a humanized antibody against CD154), and DHEA. Few studies have evaluated the efficacy of therapies during an SLE flare.Hydroxychloroquine was evaluated in a


S

Potential Rx Adjunct Mild Mod SevereHydroxychloroquine* �

Corticosteroids* � � �

ASA,* NSAIDs, anticoag �

DHEA � �

Dapsone, thalidomide � �

Azathioprine � �

Methotrexate � �

Leflunomide � �

Mycophenolate mofetil � �

Cyclophosphamide � �

IVIG/PE �

*Approved for use by the US Food and Drug Administration. anticoag=anticoagulants;ASA=acetylsalicylic acid; DHEA=dehydroepinandrosterone; IVIG/PE=intravenous immunoglobulin/plasma exchange; Mod=moderate; NSAIDs=nonsteroidal anti-inflammatory drugs.

Table 1. Lupus Treatment Options1,2

MANAGING FLARES I: TREATMENT OPTIONS FOR NONRENAL SLE FLARES

Joan T. Merrill, MD


placebo-controlled trial involving 47patients.14 Hydroxychloroquine reduced all types of flares compared to placebo, and patients receiving the drug had a relative risk of major flare of 0.43, representing a 57% reduction compared to placebo.

Bijl et al15 evaluated MMF for control of flares in 36 patients withSLE. In this study, the principal clinicalobjective was to determine whether MMF could prevent flares following arise in anti-dsDNA antibodies, which has been identified as a marker of impending relapse. Among 10 patients who had a rise in anti-dsDNA, none had a flare over the next 6 months after treatment with mycophenolate, and levelsof anti-dsDNA antibodies decreased significantly (P<0.001).

Quality-of-Life ImprovementSeveral studies have found favorableeffects of pharmacologic and nonpharma-cologic therapies on various aspects ofquality of life, including mental and sexual well-being, overall health-relatedquality of life, and fatigue. Table 2 liststhese studies.

Psychological interventions that havebeen evaluated in a few studies havedemonstrated modest results with strate-gies such as brief stress management, psy-chological education in self-efficacy andsocial support, and brief supportive/expres-sive group therapy.16-18

Emerging TherapiesNew biologic agents may offer potentialadditions to our therapeutic options forSLE. Rituximab, the anti-CD20 antibody,has been evaluated in small, phase I clini-cal trials involving patients with SLE.19 In astudy of 24 patients with severe SLE,administration of the monoclonal antibodyrituximab led to a reduction in B cells inall but one patient. The disease activityindex, serum complement 3 levels, andanti-dsDNA levels all decreased signifi-cantly. Rituximab was well tolerated, andpatients had persistent improvement in the Systemic Lupus Activity Measure. Adifferent report found less lymphopenia,decreased levels of CD27 antibodies,immunoglobulin D–containing plasmablasts,and autoreactive memory B cells after B-cell depletion and immune reconstitution.20,21

The T-cell activation modulator abata-cept is being evaluated as a potential thera-py to manage and prevent SLE flares. Inpreclinical studies in mice, abatacept pro-longed survival in murine lupus22 andenhanced the ability of cyclophosphamideto prevent renal damage.

SummarySLE is a heterogeneous, complicated, andunpredictable disease. These very factors at once dictate a critical need for new treatments and create barriers to drugdevelopment. Despite these impediments,treatments for SLE continue to advance.

References1. Dooley MA, Ginzler EM. Newer therapeutic approaches

for systemic lupus erythematosus: Immunosuppressiveagents. Rheum Dis Clin North Am. 2006;32:91-102.

2. O’Neill SG, Schreiber S. Immunotherapy of systemic lupuserythematosus. Autoimmun Rev. 2005;4:395-402.

3. Ramanujam M, Davidson A. The current status of targeting BAFF/BLyS for autoimmune diseases. Arthritis Res Ther. 2004;6:197-202.

4. Allison AC, Euqui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology.2000;47:85-118.

5. Allison AC. Immunosuppressive drugs: The first 50 years and a glance forward. Immunopharmacology.2000;47:63-83.

6. Carr SF, Papp E, Wu JC, Natsumeda Y. Characterization of human type I and type II IMP dehydrogenases. J Biol Chem. 1993;268:27286-27290.

7. Gansuage S, Breitbart A, Rinaldi N, Schwarz-Eywill M.Methotrexate in patients with moderate systemic lupuserythematosus (exclusion of renal and central nervoussystem disease). Ann Rheum Dis. 1997;56:382-385.

8. Carneiro JR, Sato EI. Double blind, randomized, placebocontrolled clinical trial of methotrexate in systemic lupuserythematosus. J Rheumatol. 1999;26:1275-1279.

9. Dooley MA. Mycophenolate mofetil: What role in the treatment of lupus? Lupus. 2006;15:179-182.

10. Chan TM, Tse KC, Tang C, Mok MY, Li FK. Long-term study of mycophenolate mofetil as con-tinuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol.2005;16:1076-1084.

11. Dooley MA, Cosio FG, Nachman PH, et al. Mycophenolatemofetil therapy in lupus nephritis. J Am Soc Nephrol.1999;10:833-839.

12. Askanase A, Tseng C, Orentas-Lein D, et al.Pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with Imuran in SLE patients. Arthritis Rheum. 2004;51(suppl):Abstract 1130.

13. Bezerra EL, Vilar MJ, da Trinidade Neto PB, Sato EI.Double-blind, randomized, controlled trial of clofazaminecompared with chloroquine in patients with systemic lupuserythematosus. Arthritis Rheum. 2005;52:3073-3078.

14. Tsakonas E, Joseph L, Esdaile JM, et al. Long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. Lupus. 1998;7:80-85.

15. Bijl M, Horst G, Bootsma H, et al. Mycophenolate mofetilprevents clinical relapse in patients with systemic lupus erythematosus at risk. Ann Rheum Dis. 2003;62:534-539.

16. Greco CM, Rudy TE, Manzi S. Effects of stress-reductionprogram on psychological function, pain, and physicalfunction of systemic lupus erythematosus patients: A randomized trial. Arthritis Rheum. 2004;51:625-634.

17. Karlson EW, Liang MH, Eaton H, et al. A randomized clinical trial of psychoeducational intervention to improve outcomes in systemic lupus erythematosus.Arthritis Rheum. 2004;50:1832-1841.

18. Dobkin PL, Da Costa D, Joseph L, et al. Counterbalancingpatient demands with evidence: Results from a pan-Canadian randomized clinical trial of brief supportive-expression group psychotherapy for women with systemiclupus erythematosus. Ann Behav Med. 2002;24:88-99.

19. Leandro MJ, Cambridge G, Edwards GC, et al. B-cell depletion in the treatment of patients with systemic lupuserythematosus: A longitudinal analysis of 24 patients.Rheumatology (Oxford). 2005;44:1542-1545.

20. Looney RJ, Anolik JH, Campbell D, et al. B cell depletionas a novel treatment for systemic lupus erythematosus: A phase I/II dose-escalation trial of rituximab. ArthritisRheum. 2004;50:2580-2589.

21. Anolik JH, Bernard J, Cappione A, et al. Rituximabimproves peripheral B cell abnormalities in human systemic erythematosus. Arthritis Rheum. 2004;50:3580-3590.

22. Daikh DI, Wofsy D. Cutting edge: Reversal of murine lupus nephritis with CTLA-4Ig and cyclophosphamide. J Immunol. 2001;166:2913-2916.


Table 2. Prospective Randomized Studies Involving Quality of Life

Rx n Placebo Results Ref

Improved Nordmark.DHEA 41 yes mental + sexual Autoimm.

well-being 2005;36:531.

Improved Strand. LJP 394 179 yes HRQOL Lupus. 2003;

12:671.

Graded Tench.

aerobic 93 relaxation Improved Rheum

exercise or none fatigue Oxford. 2003;42:1050.

MMF vs MMF improvedCyclophos- 12 crossover improved fatigue Tse. Lupus.

phamide and QOL 2006;15:371.

DHEA= dehydroepiandrosterone; HRQOL= health-related quality of life;MMF=mycophenolate mofetil; QOL=quality of life.


s many as two thirds of patients with systemic lupus erythematosus(SLE) have renal flares,1 which

can lead to loss of kidney function, kidneyfailure, and the need for dialysis. Promptinitiation of immunosuppressive therapywith intravenous (IV) cyclophosphamidecan control renal flares but at a potentially significant cost in terms of dollars and toxicity. Effective maintenance therapy isessential to reduce the risk of relapse after a flare has been brought under control. However, the optimal maintenancetherapy has yet to be determined. Clinicalinvestigation of mycophenolate mofetil(MMF) has suggested superiority over IVcyclophosphamide for maintaining remis-sion in patients with lupus nephritis.Whether MMF is more effective than other maintenance regimens for long-termpreservation of renal function has not yet been established.

Remission and RelapseAchieving and maintaining remission hasemerged as the key to improved patient and renal survival in lupus nephritis. In astudy of 86 patients with severe lupusnephritis, Korbet and colleagues2 showedthat 37 patients who achieved remissionwith high-dose prednisone and oral cyclo-phosphamide or this regimen plus plasma-pheresis had a 95% overall survival rateafter 5 and 10 years of follow-up, whereasthe patients in the study who did notachieve remission had a 69% survival at 5years, declining to 60% at 10 years. Renalsurvival remained stable at 94% at 5 and 10years in the remission group compared to45% at 5 years and 31% at 10 years in thenonremission group.

The standard National Institutes ofHealth regimen for lupus nephritis includes six monthly doses of IV cyclophosphamide as induction therapy, implying that remission should be achieved within 6 months. Available datasuggest otherwise. For example, Ioannidiset al3 found a median time to remission of10 months with IV cyclophosphamide, and22% of patients in their study failed toachieve remission after 2 years. Althoughthe median time to relapse after remissionin the Ioannidis study was 79 months, 20% of patients relapsed within the first 18 months.

Other studies have demonstrated widevariation in relapse rates and time torelapse. In one of the larger studies con-ducted to evaluate relapse in treated lupusnephritis, the relapse rate was 45% and the

median time to relapse was 36 months (18months in partial responders).4

Several predictors of renal flares inpatients with lupus nephritis have been welldocumented. Of note, virtually all studiesthat specifically evaluated the timing oftherapy showed that a delay in institutingtreatment is as important in predicting renalflares as the time required to achieve aremission.

One recent study5 highlighted the roleof duration of therapy in achieving a remission and predicting relapse. Patientswho did not flare were treated for a median of 57 months compared to 30months of treatment for patients who hadflares (P<0.009). Moreover, patients whodid not have flares continued treatment fora median of 24 months after they achievedremission, compared to 12 months in thegroup that had flares (P<0.02).5

Several considerations are involved in distinguishing between worsening of a patient’s prior renal status and the occurrence of a flare. The clinician firstmust establish the patient’s initial presenta-tion of lupus nephritis, which usually can be determined from the medical record. Second, the patient’s remission status after a flare must be characterized,beginning with the determination ofwhether the patient achieved a com-plete response or had stabilization ofabnormalities. (For example, if the patienthad a complete response, how was thatdefined? Did the definition go beyond clinical and immunologic parameters and include repeat biopsies?) Third, it must be determined whether the patient haspersistent serologic activity withoutchanges in clinical status, which suggests apoorer treatment outcome and greater like-lihood of relapse. Finally, it must be deter-mined whether the patient has had deterio-ration of renal function in the absence ofimmunologic or clinical exacerbation ofrenal disease that would suggest a flare.

Need for Therapy AlternativesCyclophosphamide has been shown toinduce remission in patients who haveactive lupus nephritis. However, the drughas several disadvantages that have driventhe search for effective alternatives.Cyclophosphamide is associated with myr-iad toxicities affecting multiple organ sys-tems. Racial and ethnic differences inresponse to the drug clearly exist. Studiesalso have documented socioeconomic dif-ferences in outcomes of treatment with IVcyclophosphamide.6,7

Emergence of Mycophenolate MofetilMMF is a reversible inhibitor of inosinemonophosphate dehydrogenase, a rate-limiting enzyme in purine synthesis. MMF has selective effects on lymphocytes,including inhibition of B- and T-cell proliferation, antibody formation, andexpression of adhesion molecules and other cytokines. The drug is approved forprevention of transplant rejection. Datafrom murine models of lupus suggest that MMF improves survival and helps preserve renal function.8,9

Several factors provide a rationale for use of MMF to treat lupus nephritis. As noted above, a clear need exists for acyclophosphamide alternative that is just aseffective but safer. Unlike a new drug stillin development, MMF has been commer-cially available for more than a decade, dur-ing which time its clinical activity and side-effect profile have been well defined. Soonafter MMF became available, anecdotalreports suggested efficacy in patients withlupus nephritis unresponsive to steroids andIV cyclophosphamide.

EARLY STUDIES. Preliminary clinical com-parisons against cyclophosphamide provid-ed reason for optimism about MMF as apotential alternative therapy for lupusnephritis. In one study,10 42 patients with class IV lupus nephritis were treated with oral cyclophosphamide orMMF. Both therapies were associated with about an 80% response rate and similar toxicity profiles. Investigators inanother preliminary clinical trial11 treated46 patients with biopsy-proven diffuse proliferative lupus nephritis with IVcyclophosphamide or MMF. MMF led togreater improvement in proteinuria, urinaryred blood cell counts, anti-DNA titers, andrenal biopsy results and was associatedwith fewer adverse reactions.

MULTICENTER TRIAL. Concurrent with thepublication of these studies, the US Foodand Drug Administration (FDA), throughthe agency’s Orphan Products Program,supported a multicenter, randomized clini-cal trial to compare MMF, 3 g/day, andmonthly IV cyclophosphamide in escalat-ing doses up to 1 g/m2, as induction therapyfor lupus patients with an active flare ofclass III, IV, or V lupus nephritis.12 The trialwas designed to test the hypothesis thatMMF has equivalent efficacy with superiortoxicity/tolerability compared to IV cyclo-phosphamide.

The trial involved 140 patients who


AMANAGING FLARES II: TREATMENT OPTIONS FOR RENAL FLARES

Ellen M. Ginzler, MD, MPH


were treated in an open-label study design for 24 weeks. The results showedthat 16 of 71 patients in the MMF groupachieved complete remissions compared to4 of 69 patients randomized to cyclophos-phamide (P=0.005). When complete andpartial remissions were combined, 37 of 71 patients treated with MMF responded to therapy versus 21 of 69 in the cyclophos-phamide group (P=0.009).

Because of evidence of poorer absorp-tion of the drug in African Americans, thestudy protocol called for a higher targetdose of MMF than that used in any previ-ous studies. Gastrointestinal (GI) sideeffects were common but did not result instudy withdrawal: nausea, vomiting, andbloating were controlled in most cases bygradual dose escalation or treatment with a proton pump inhibitor. Diarrhea wasmore common with MMF than with IVcyclophosphamide, but most episodes weremild and self-limited. Infections occurredless often with MMF than with cyclophos-phamide. One patient in the MMF groupdeveloped a severe rash that recurred onrechallenge and led to discontinuation.

The principal conclusions of the study were that MMF was more effectiveand better tolerated than was IV cyclophos-phamide for induction therapy of lupusnephritis.

OTHER STUDIES. In another recent study,13

44 patients with proliferative lupus nephritis were randomized to MMF, 2g/day, or monthly IV cyclophosphamide,0.75 to 1.0 g/m2, for 6 months. The totalresponse rate (complete and partial remis-sions) was similar in both treatment groups(58% with MMF, 52% with cyclophos-phamide), but a greater proportion ofpatients achieved complete remissions withMMF (26% vs 12%). Adverse events weresimilar in the two treatment groups.

MMF was compared with IV cyclo-phosphamide and azathioprine as mainte-nance therapy after IV cyclophosphamideinduction in patients with proliferativelupus nephritis (Figure).14 The studyinvolved 59 patients who were followed foras long as 30 months after response toinduction therapy. For the primary endpoint of freedom from renal relapse, MMF proved superior to IV cyclophos-phamide (P=0.021) and equivalent to azathioprine. Hospitalization, amenorrhea,infection, and GI side effects occurredless often with MMF and azathioprinethan with cyclophosphamide.

Follow-up data from one of the preliminary clinical studies suggested that early relapse occurred more often with MMF than with oral cyclophos-phamide. In that trial, the MMF dose was decreased after 6 mon ths , and

patients on oralcyclophosphamidewere switched toazathioprine. Inresponse to thisobservation, theMMF dose wastapered more grad-ually, and, after fol-low-up for an aver-age of 63 months,the flare rate wassimilar in the twotreatment groups.15

Unresolved IssuesSeveral questionsrelated to MMFtherapy for lupusnephritis remain tobe answered. With regard to induction ther-apy, the potential value of continuing thera-py in patients who do not respond by 6months has not been determined. In theclinical arena of MMF maintenance thera-py, issues involving the optimal duration oftherapy, dose reduction in respondingpatients, and MMF maintenance after IVcyclophosphamide have not been resolved.Whether MMF is superior to other poten-tial maintenance regimens with regard tolong-term renal preservation also has notbeen established.

Emerging TherapiesSeveral FDA-approved drugs are beingused off-label and investigationally for thetreatment of lupus nephritis. They includerituximab, abatacept, and leflunomide. Inaddition, several investigational agents willbe evaluated in upcoming clinical trials,including belimumab, epratuzumab, andedratide.

SummaryRenal flares are common in patients with lupus nephritis. Therapy that achieves a complete remission reduces the likelihood of flares. IV cyclophos-phamide has been the standard of care for treating lupus nephritis, but toxicity has fueled a search for safer alternativesthat are equally effective. In preliminarystudies, MMF has demonstrated efficacyand tolerability that are superior to those of cyclophosphamide. The optimalmaintenance therapy regimen has yet to be determined. Several other approvedmedications are being used off-label fortreatment of lupus nephritis, and their efficacy and safety have not yetbeen established. In addition, a num-ber of investigational agents, particu-larly biologics, will be evaluated inclinical trials involving patients withlupus nephritis.

References1. Sidiropoulos PI, Kritikos HD, Boumpas DT. Lupus

nephritis flares. Lupus. 2005;14:49-52.

2. Korbet SM, Lewis EJ, Schwartz MM, et al. Factors predicting outcome in severe lupus nephritis. LupusNephritis Collaborative Study Group. Am J Kidney Dis.2000;35:904-914.

3. Ioannidis JP, Boki KA, Katsorida ME, et al. Remission,relapse, and re-remission of proliferative lupus nephritistreated with cyclophosphamide. Kidney Int. 2000;57:258-264.

4. Illei GG, Takada K, Parkin D, et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy:Long-term followup of a cohort of 145 patients participating in randomized controlled studies. ArthritisRheum. 2002;46:995-1002.

5. Moroni G, Gallelli B, Quaglini S, et al. Withdrawal of therapy in patients with proliferative lupus nephritis: Long-term follow-up. Nephrol Dial Transplant.2006;21:1541-1548.

6. Barr RG, Seliger S, Appel GB, et al. Prognosis in proliferative lupus nephritis: The role of socio-economicstatus and race/ethnicity. Nephrol Dial Transplant.2003;18:2039-2046.

7. Hopkinson ND, Jenkinson C, Muir RR, Doherty M, Powell RJ. Racial group, socioeconomic status, and the development of persistent proteinuria in systemic lupuserythematosus. Ann Rheum Dis. 2000;59:116-119.

8. Corna D, Morigi M, Facchinetti D, et al. Mycophenolatemofetil limits renal damage and prolongs life in murine lupus autoimmune disease. Kidney Int.1997;51:1583-1589.

9. Van Buggen MC, Walgreen B, Rijke TP, Berden JH.Attenuation of murine lupus nephritis by mycophenolatemofetil. J Am Soc Nephrol. 1998;9:1407-1415.

10. Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolatemofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343:1156-1162.

11. Hu W, Liu Z, Chen H, et al. Mycophenolate mofetil vscyclophosphamide therapy for patients with diffuse prolif-erative lupus nephritis. Chin Med J. 2002;115:705-709.

12. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolatemofetil or intravenous cyclophosphamide for lupus nephri-tis. N Engl J Med. 2005;353:2219-2228.

13. Ong LM, Hooi LS, Lim TO, et al. Randomized controlled trialof pulse intravenous cyclophosphamide versus mycopheno-late mofetil in the induction therapy of proliferative lupusnephritis. Nephrology. 2005;10:504-510.

14. Contreras G, Pardo V, Leclerq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med.2004;350:971-980.

15. Chan TM, Tse KC, Tang CS, et al. Long-term study ofmycophenolate mofetil as continuous induction and main-tenance treatment for diffuse proliferative lupus nephritis.J Am Soc Nephrol. 2005;16:1076-1084.


p = 0.021, MMF vs IVCp = 0.124, AZA vs IVCp = 0.222, MMF vs AZA

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Copyright © 2007 Elsevier Inc.

Renal and Nonrenal Flares in Systemic Lupus Erythematosus:Meeting the Clinical Challenge

1. The clinical course of systemic lupus erythematosus (SLE) usually evolves overhow many years?A. A critical 5-year period of adolescenceB. A 10-year period from adolescence to early adulthoodC. A period of 20 to 40 yearsD. The clinical course is unpredictable

2. Which of the following factors predicts a poor prognosis in SLE?A. Proliferative nephritisB. Development of severe diseaseC. Presence of antiphospholipid antibodiesD. No improvement in creatinine/proteinuria after 6 months of treatmentE. All of the above

3. Which of the following drugs is approved for treatment of SLE?A. HydroxychloroquineB. CyclophosphamideC. Mycophenolate mofetilD. Azathioprine

4. Treatment for SLE should aim to:A. Suppress an overactive immune systemB. Restore balance to the immune systemC. Normalize lymphocyte countsD. Reduce inflammation

5. Which of the following is/are the most common disease pattern of SLE?A. Relapsing/remittingB. Chronic activityC. Long quiescenceD. All of the above.

6. The two most common target organ systems of SLE are:A. Skin and kidneyB. Musculoskeletal and kidneyC. Kidney and cardiovascularD. Skin and musculoskeletal

7. What is the key factor in prolonging patient and renal survival in patients with SLE?A. Reducing inflammationB. Reducing levels of autoantibodiesC. Achieving and maintaining remissionD. Improving creatinine/proteinuria levels

8. A multicenter, randomized clinical trial comparing IV cyclophosphamide and mycophenolate mofetil (MMF) as induction therapy for lupus nephritis showed that:A. IV cyclophosphamide remains the most potent drug therapy

available for lupus nephritisB. IV cyclophosphamide and MMF are equally effective and toleratedC. MMF is better tolerated and more effective than IV cyclophosphamideD. MMF is too toxic for chronic treatment of SLE

CME Post-TestInstructions: On the answer sheet, please darken the circle of the one answer to each question that is true. To obtain credit, you must have 70 percent or more of the answers cor-rect. For participants who pass the test, please allow 4 weeks after returning the post-test and evaluation form to receive your certificate. Completed answer sheets/program evalu-ations should be returned as indicated on the form. Credit is available through February 15, 2008. Non-US physicians can claim CME credit for this program.

Estimated time to complete: 1 hour.

1. How would you rate this activity overall? (5=excellent, 1=poor; please circle one) 5 4 3 2 12. In your opinion, did you perceive any commercial bias? � Yes � No

If yes, please explain. ___________________________________________________________________________________________________________________________3. Do you plan on making any changes in your practice as a result of this activity? � Yes � No

If yes, please explain. ___________________________________________________________________________________________________________________________May we contact you in the future to determine if you made changes? � Yes � No

4. Do you feel each of the following objectives was met?• list the signs, symptoms, and clinical impact of SLE. � Yes � No � Partially � N/A• outline the clinical course of SLE, the importance of renal and nonrenal flares, � Yes � No � Partially � N/A

and how flares are defined.• state the treatment options for both nonrenal and renal flares and explain the � Yes � No � Partially � N/A

importance and benefits of early treatment.• describe the management of nonrenal clinical features of SLE. � Yes � No � Partially � N/A

5. Do you feel that the information in this activity was based on the best evidence available? � Yes � No If no, please explain. ___________________________________________________________________________________________________________________________

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