Table 1.

Authors	Sample size	Methodology	Key findings
Buyon et al.(see in text reference)	351	Double-blind, placebo-controlled study	Results suggest that exogenous estrogen can increase disease activity, but the effect is only recognized in mild/moderate flares. These data suggest that female hormones may play a role in pathogenesis of SLE.
Tseng et al.^[3]	180	Double-blind, placebo-controlled study	This study suggests that elevation in C3a and dsDNA predict flares, and short-term, moderate doses of PDN prevent severe flares and exposure to high-dose steroids.
Kapitsinou et al. ^[15*]	18	Retrospective study	The conclusion of this study is that MMF appears to be a safe and efficacious alternative treatment in proliferative SLE nephritis, whereas its efficacy in lupus membranous nephropathy remains unclear.
Riskalla et al.^[16]	54	Retrospective study	In this study the majority of patients tolerated MMF in a range of doses and showed clinical improvement, suggesting that flexible dose scheduling should be considered when using MMF in patients with SLE.
Doria et al. ^[17*]	42	Prospective uncontrolled study	In this study MMF seems to be well tolerated and effective in patients with refractory disease and no different from standard therapy in maintaining GN remission over 9 months of follow-up.
Ginzler et al. ^[21**]	140	Prospective, multicentric, controlled study	The conclusion of this trial was that MMF is better tolerated than IV CYC, with fewer pyogenic or other serious infections; GI side effects did not limit the tolerability of MMF.
Contreras et al. ^[22**]	59	Prospective, controlled study	The conclusion of this study was that for patients with proliferative lupus nephritis, short-term therapy with IV CYC followed by maintenance therapy with MMF or azathioprine appeared to be more efficacious and safer than long-term therapy with IV CYC.
Alarcon-Segovia et al. ^[31**]	230	Randomized, placebo-controlled trial	LJP appeared to be well tolerated; the rate of adverse events was similar to placebo. One patient died in each group. In patients with creatinine more than 1.5 mg/dL, the placebo group had a higher percentage of flares. Higher doses of drug had a better response.
Lisukov et al. ^[38*]	6	Case series	This case series concludes that high-dose immunosuppression with autologous stem cell transplantation achieves prolonged, corticosteroid-free remissions, and that a more judicious selection of patients with less severe disease but with a high risk of relapse or further progression will diminish transplant-related mortality.
Petri et al. ^[40*]	14	Prospective, uncontrolled study	The conclusion was that cyclophosphamide without stem cell transplantation led to rapid hematopoietic reconstitution and has significant clinical benefit in patients with refractory disease.
Karassa et al.^[43]		Meta-analysis	The conclusion of this meta-analysis is that several aspects of the design and reporting of RCT on SLE can be improved, with larger, adequately powered and accurately reported trials needed.

Recent Controlled Trials and Case Series

CYC, cyclophosphamide; GI, gastrointestinal; GN, glomerulonephritis; IV, intranvenous; MMF, mycophenolate mofetil; PDN, prednisone; RCT, randomized controlled trial; SLE, systemic lupus erythematosus.

Petri M, Lahita RG, van Vollenhoven RF, et al.: Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus. Arthritis Rheum 2002, 46:1820-1829.
Chang DM, Lan JL, Lin HY, et al.: Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus. Arthritis Rheum 2002, 46:2924-2927.
* Tseng C, Buyon J, Belmont HM, et al.: Moderate dose steroids prevent severe flares of serologically active, clinically stable SLE patients. Arthritis Rheum 2003, 48:S260. In stable patients with SLE, changes in C3a and anti-dsDNA levels are predictive of clinical flares, which can be suppressed with moderate-dose steroids.
Houssiau FA, Vasconcelos C, D'Cruz D, et al.: Immunosuppressive therapy in lupus nephritis. The Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002, 46:2121-2131.
Illei GG, Takada K, Parkin D, et al.: Renal flares are common in patients with severe proliferative lupus nephritis treated with immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum 2002, 46:995-1002.
Al Salloum AA: Cyclophosphamide therapy for lupus nephritis: poor renal survival in Arab children. Pediatr Nephrol 2003, 18:357-361.
Lehman TJ, Edelheit BS, Onel KB: Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis. Ann Rheum Dis 2004, 63:321-323.
Barbano G, Gusmano R, Damasio B, et al.: Childhood-onset lupus nephritis: a single-center experience of pulse intravenous cyclophosphamide therapy. J Nephrol 2002, 15:123-129.
Dooley MA, Hogan S, Jennette C, et al.: Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Kidney Int 1997, 51:1188-1195.
Williams W, Bhagwandass A, Sargeant LA, et al.: Severity of systemic lupus erythematosus with diffuse proliferative glomerulonephritis and the ineffectiveness of standard pulse intravenous cyclophosphamide therapy in Jamaican patients. Lupus 2003, 12:640-645.
Velasquez X, Verdejo U, Massardo L, et al.: Outcome of Chilean patients with lupus nephritis and response to intravenous cyclophosphamide. J Clin Rheumatol 2003, 9:7-14.
* Barr RG, Seliger S, Appel GB, et al.: Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity. Nephrol Dial Transplant 2003, 18:2039-2046. This retrospective review of a large series of patients with proliferative lupus nephritis points out the important association of poverty with poor outcome.
Alba P, Karim MY, Hunt BJ: Mycophenolate mofetil as a treatment for autoimmune hemolytic anemia in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 2003, 12:633-635.
Samad AS, Lindsley CB: Treatment of pulmonary hemorrhage in childhood systemic lupus erythematosus with mycophenolate mofetil. South Med J 2003, 96:705-707.
* Kapitsinou PP, Boletis JN, Skopouli FN, et al.: Lupus nephritis: treatment with mycophenolate mofetil. Rheumatology 2004, 43:377-380. In this retrospective review of 18 patients with LN, MMF appeared to be safe and effective in those with proliferative histology, whereas efficacy in membranous LN was not observed.
* Riskalla M, Somers EC, Fatica RA, et al.: Tolerability of mycophenolate mofetil in patients with systemic lupus erythematosus. J Rheumatol 2003, 30:1508-1512. This retrospective review of 54 consecutive patients treated with MMF describes the most common side effects of this agent and the reasons for drug discontinuation.
* Doria A, Frassi M, Della Libera S, et al.: Prospective study on tolerability and efficacy of mycophenolate mofetil (MMF) in SLE. Arthritis Rheum 2003, 48:S587. This prospective review of 42 patients, some with refractory manifestations of active lupus and others with newly diagnosed nephritis, found MMF therapy to be well tolerated and effective in reducing overall disease activity.
Ferro ML, Karim MY, Abbs IC, et al.: Mycophenolate mofetil: a potential treatment for reducing proteinuria associated with membranous lupus nephritis. Arthritis Rheum 2003, 48:S588.
Chan TM, Li FK, Tang CSO, et al.: Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000, 343:1156-1162.
Hu W, Liu Z, Chen H, et al.: Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chin Med J 2002, 115:705-709.
** Ginzler EM, Aranow C, Merrill JT, et al.: Toxicity and tolerability of mycophenolate mofetil (MMF) versus intravenous cyclophosphamide (IVC) in a multicenter trial as induction therapy for lupus nephritis (LN). Arthritis Rheum 2003, 48:S586. In a randomized, open-label trial of 140 patients with severe LN, MMF was found to be superior to IV CYC in inducing complete remissions, with better patient tolerability.
** Contreras G, Pardo V, Leclercq B, et al.: Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004, 350:971-980. In patients with proliferative LN, induction therapy with IV CYC followed by maintenance therapy with either MMF or AZA appeared to be more efficacious and safer than long-term IV CYC.
Saito K, Nawata M, Nakayamada S, et al.: Successful treatment with anti-CD20 monoclonal antibody (rituximab) of life-threatening refractory systemic lupus erythematosus with renal and central nervous system involvement. Lupus 2003, 12:798-800.
Saigal K, Valencia IC, Cohen J, et al.: Hypocomplementemic urticarial vasculitis with angioedema, a rare presentation of systemic lupus erythematosus: rapid response to rituximab. J Am Acad Dermatol 2003, 49:S283-S285.
Perrotta S, Locatelli F, La Manna A, et al.: Anti-CD20 monoclonal antibody (rituximab) for life-threatening autoimmune hemolytic anemia in a patient with systemic lupus erythematosus. Br J Haematol 2002, 116:465-467.
Weide R, Heymans J, Pandorf A, et al.: Successful long-term treatment of systemic lupus erythematosus with rituximab maintenance therapy. Lupus 2003, 12:779-782.
* Eisenberg R: Rituximab in lupus. Arthritis Res Ther 2003, 5:157-159. This review outlines the pathophysiologic basis for which rituximab has been used in the treatment of SLE.
Leandro MJ, Edwards JE, Cambridge G, et al.: An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002, 46:2673-2677.
Leandro MJ, Ehrenstein MR, Edwards JCW, et al.: Treatment of refractory lupus nephritis with B lymphocyte depletion. Arthritis Rheum 2003, 48:S378.
Anolik JH, Campbell D, Felgar R, et al.: B lymphocyte depletion in the treatment of systemic lupus (SLE); phase I/II trial of rituximab (Rituxan in SLE). Arthritis Rheum 2002, 46:S717.
** Alarcon-Segovia D, Tumlin AJ, Furie R, et al.: LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus. Arthritis Rheum 2003, 48:442-454. LJP 394, a B-cell tolerogen against anti-dsDNA antibodies, was compared with placebo in a large trial of patients with prior LN. A difference in flare rates did not reach statistical significance.
Strand V, Aranow C, Cardiel MH, et al.: Improvement in health-related quality of life in systemic lupus erythematosus patients enrolled in a randomized clinical trial comparing LJP 394 treatment with placebo. Lupus 2003, 12:677-686.
Furie R, Stohl W, Ginzler E, et al.: Safety, pharmacokinetics and pharmacodynamic results of a phase I single and double dose-escalation study of LymphoStat B (human monoclonal antibody to BLyS) in SLE patients. Arthritis Rheum 2003, 48:S377.
Hirashima M, Fukasawa T, Abe K, et al.: Expression and activity analyses of CTLA4 in peripheral blood lymphocytes in systemic lupus erythematosus patients. Lupus 2004, 13:24-31.
Foell J, Strahontin S, O'Neil SP, et al.: CD137 costimulatory T cell receptor engagement reverses acute disease in lupus prone NZB x NZW F1 mice. J Clin Invest 2003, 111:1505-1518.
Genovese MC, Uhrin Z, Bloch DA, et al.: Long-term follow-up of patients treated with total lymphoid irradiation for lupus nephritis. Arthritis Rheum 2002, 46:1014-1018.
Traynor AE, Barr WG, Rosa RM, et al.: Hematopoietic stem cell transplantation for severe and refractory lupus. Analysis after five years and fifteen patients. Arthritis Rheum 2002, 46:2917-2923.
* Lisukov IA, Sizikova SA, Kulagin AD, et al.: High-dose immunosuppression with autologous stem cell transplantation in severe refractory systemic lupus erythematosus. Lupus 2004, 13:89-94. This series of six SLE patients treated with stem cell transplantation suggests that long-term, steroid-free remissions are possible, but early mortality is not uncommon.
* Petri M, Jones RJ, Brodsky RA: High-dose cyclophosphamide without stem cell transplant in systemic lupus erythematosus. Arthritis Rheum 2003, 48:166-173. In an uncontrolled series of 14 patients with refractory features of SLE, high-dose CYC without stem cell transplantation resulted in rapid hematopoietic reconstitution with significant clinical benefit.
** Karassa FB, Tatsioni A, Ioannidis JPA: Design, quality, and bias in randomized controlled trials of systemic lupus erythematosus. J Rheumatol 2003, 30:979-984. This excellent review of all published, randomized, clinical trials in SLE identifies the problematic issues in the design and reporting of studies, which need to be considered in improving the quality of subsequent trials.
Bronson K, Petri M, Brodsky R, et al.: High-dose cyclophosphamide is preferable to monthly IV cyclophosphamide at six months. Arthritis Rheum 2003, 48:S588.
Edworthy SM, Dobkin PL, Clarke AE, et al.: Group psychotherapy reduces illness intrusiveness in systemic lupus erythematosus. J Rheumatol 2003, 30:1011-1016.
Tench CM, McCarthy J, McCurdie, et al.: Fatigue in systemic lupus erythematosus: a randomized controlled trial of exercise. Rheumatology 2003, 42:1050-1054.

CME

Systemic Lupus Erythematosus Trials: Successes and Issues

Authors: Ellen M Ginzler, MD; Ioana Moldovan, MD
THIS ACTIVITY HAS EXPIRED FOR CREDIT

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Target Audience and Goal Statement

This activity is intended for primary care physicians and rheumatologists who care for patients with systemic lupus erythematosus (SLE).

The goal of this activity is to update physicians on the use of standard-care therapies and new agents for SLE and its complications.

Upon completion of this activity, participants will be able to:

List current pharmacologic and nonpharmacologic treatment options for SLE.
Describe limitations and shortcomings of clinical trials on SLE therapies.
Outline the outcomes measures used for determining efficacy of SLE therapies.
List complications of SLE and the main causes of morbidity and mortality.
Identify new agents being developed for SLE and their mechanisms of action.

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Author(s)

Ellen M Ginzler, MD

Rheumatology Division, SUNY Downstate Medical Center, Brooklyn, New York, USA

Disclosures

Disclosure: Ellen M. Ginzler, MD, has no significant financial interests or relationships to disclose.

Ioana Moldovan, MD

Rheumatology Division, SUNY Downstate Medical Center, Brooklyn, New York

Disclosures

Disclosure: Ioana Moldovan, MD, has no significant financial interests or relationships to disclose.

CME Author(s)

Désirée Lie, MD, MSEd

Clinical Professor of Family Medicine; Director, Division of Faculty Development, University of California, Irvine School of Medicine, Irvine, California

Disclosures

Disclosure: Désirée Lie, MD, MSEd, has no significant financial interests or relationships to disclose.

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Abstract and Introduction

Abstract

Purpose of Review: The purpose of this review is to discuss the most recent published clinical trials for systemic lupus erythematosus and to identify important issues that have arisen in association with the search for new therapies for systemic lupus erythematosus, as well as new regimens or indications for the use of standard-of-care agents such as corticosteroids and cyclophosphamide.
Recent Findings: Important developments have occurred during the past 2 years as interest in this area has increased, largely because of the participation of pharmaceutical and biotechnical companies in the development and testing of novel agents for systemic lupus erythematosus. Several important large-scale, multicenter, randomized controlled trials have been completed, but none has yet resulted in a new, approved indication for systemic lupus erythematosus. Many issues in the identification of new therapeutic modalities remain. These include the fact that a majority of published reports include either small numbers of patients in controlled trials that lack statistical power to draw conclusions, or are uncontrolled anecdotal series or individual case reports. Among the larger controlled trials, a pervasive issue in the failure to reach statistical significance may be the initial study design. Inclusion of patients with mild and/or stable disease activity does not allow for an effect size sufficient to show differences in treatment arms without recruitment of very large numbers of subjects. Finally, several potentially important trials have been reported only in abstract form to date. Further assessment of the results must await formal publication of these studies.

Introduction

Clinicians interested in new developments in the challenging treatment of systemic lupus erythematosus (SLE) should find this review useful. SLE is a complex disease, and investigators designing clinical trials are faced with an array of manifestations and difficult-to-measure response to treatment. Ideally, the protocols for clinical trials and ultimate therapeutic decisions should be guided by evidence-based medicine, considering the pathophysiologic mechanisms and epidemiologic principles that influence the clinical course. Few large-scale, prospective, randomized studies have been published, most of them addressing lupus nephritis as the disease manifestation, with better defined end points such as changes in serum creatinine, urine protein excretion, development of end-stage renal disease, and death. Our goal is to provide a comprehensive review of the clinical trials and relevant case series in SLE published during the past 2 years, outlining the important developments and reinforcing some of the most significant issues that arise.

Page 1 of 7

Hormonal Considerations

References

Table 1.

References

Faculty and Disclosures

Author(s)

Ellen M Ginzler, MD

Ioana Moldovan, MD

CME Author(s)

Désirée Lie, MD, MSEd

CME

Systemic Lupus Erythematosus Trials: Successes and Issues

Target Audience and Goal Statement

Disclosures

Author(s)

Ellen M Ginzler, MD

Ioana Moldovan, MD

CME Author(s)

Désirée Lie, MD, MSEd

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Systemic Lupus Erythematosus Trials: Successes and Issues

Abstract and Introduction

Abstract

Introduction

Table of Contents