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ACR 2007 Update on Treatment Advances for Systemic Lupus Erythematosus

Authors: Doruk ErkanFaculty and Disclosures

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Introduction

There has been no US Food and Drug Administration (FDA)-approved medication for systemic lupus erythematosus (SLE) for more than 30 years. However, we have entered a new era in lupus management in that targeted therapies, including biologic agents, have been studied in randomized clinical trials with the hope that there will be more effective and less toxic treatment options for lupus patients in the near future. In this context, the 2007 American College of Rheumatology (ACR) meeting, which was held in Boston, Massachusetts, with approximately 14,000 attendees, gave us a glimpse of the future on lupus management.

Mycophenolate Mofetil

Mycophenolate mofetil (MMF), via its active metabolite mycophenolic acid, inhibits T- and B-cell proliferation as well as the expression of adhesion molecules. Dr. Ellen Ginzler from the SUNY-Downstate Medical Center, New York, NY, presented the results of the induction phase of the prospective, randomized, controlled, multicenter phase 3 Aspreva Lupus Management Study (ALMS).[1] Given that MMF has been increasingly used in the management of lupus patients, the results of this study were of great interest for attendees.

The primary objective of the open-label, 24-week induction phase of ALMS was to determine the efficacy of MMF compared with intravenous (IV) cyclophosphamide (CYC) for inducing response in lupus nephritis patients (class III, IV, or V). Three hundred seventy lupus nephritis patients (147 [39.7%] whites, 123 [33.2%] Asians, and 100 [27%] others [mostly African Americans or mixed race]) were randomized to either MMF (target dose 3 g/day) or IV CYC (0.5-1.0 g/m2); all patients received concomitant corticosteroids (0.75-1 mg/kg/day with protocol-determined tapering). The definition of response was "decrease in proteinuria (urine protein/creatinine ratio) and improvement/stabilization of the serum creatinine"; the response rates at 24 weeks were 56.2% (104/185) in the MMF arm and 53% (98/185) in the IV CYC arm (odds ratio [OR] 1.2, 95% confidence interval [CI] 0.8-1.8, P = .575 ). Given that the study was powered as a superiority trial (ie, MMF is more efficacious than IV CYC) from a statistical point of view, the trial failed to prove its primary hypothesis.

However, when investigators performed a post hoc subgroup analysis that was based on the racial/ethnic distribution of the study participants, although the response rates (MMF vs IV CYC) were similar for white and Asian patients, the response rate to MMF vs IV CYC was significantly higher among patients classified as "other" (60.4% vs 38.5%, OR 2.4, 95% CI 1.1-5.4, P = .033). Furthermore, when the study results were further analyzed, comparing data among the Hispanic and non-Hispanic ethnic population (the 2 groups had similar baseline clinical characteristics), the response rate to MMF vs IV CYC among Hispanic patients (131/370) was significantly higher than the response rate among non-Hispanics (60.9% vs 38.8%, OR 2.5, 95% CI 1.2-5.1, P = .011).

The secondary objective of the induction phase of ALMS was to characterize the safety of MMF compared with IV CYC over the 24-week period. Although there were more infections, adverse events, serious adverse events, and deaths among patients who received MMF, the results were not statistically significant between the 2 groups.

On the basis of the results of the induction phase of ALMS, the investigators concluded that although the response rates of lupus nephritis patients to MMF and IV CYC were comparable, racial and ethnic differences may be a key determinant of the response to MMF because more nonwhite and non-Asian patients responded to MMF than IV CYC.

The primary objective of the ongoing double-blind maintenance phase of the study is to determine the long-term efficacy of MMF compared with azathioprine in maintaining remission and renal function in lupus nephritis patients.[2] Of note, another randomized multicenter trial comparing MMF and azathioprine as remission-maintenance treatment (after induction with IV CYC) for proliferative lupus nephritis is also in progress.[3]

Belimumab

Belimumab is a fully human monoclonal antibody that binds and inhibits soluble BLyS (a B-lymphocyte stimulator that promotes B-cell survival and differentiation). Dr. Michelle Petri from Johns Hopkins University, Baltimore, Maryland, presented the 2.5-year follow-up data on a prospective, randomized, double-blind, placebo-controlled, multicenter, 52-week, phase 2 trial in which patients were recruited to an open-label extension period after 52 weeks.[4] This study was designed to evaluate the safety and efficacy of belimumab in lupus patients; the primary endpoints were percentage of change at week 24 in the Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) SLE Disease Activity Index (SLEDAI) scores and the time to first lupus flare over 52 weeks.

In 2 poster presentations, the serologic characteristics and safety data were discussed. Dr. William Stohl from the University of Southern California, Los Angeles, presented data to show that when compared with placebo-treated study participants (n = 133), belimumab-treated participants (n = 336) were more likely to have significant improvements in laboratory parameters.[5] Of note, patients received 3 different IV doses of belimumab during the phase 2 study, and no significant dose-response relationship was identified. Belimumab-treated patients had significant immunoglobulin, anti-double-strand DNA, anti-Smith antibodies, and anti-RNP reductions at weeks 52 and 128 as well as significant complement 3/4 level increases at weeks 52, 76, 96, and 128 (on the basis of the subset of participants with low complement 3/4 levels at baseline). In the presentation by Dr. Joan Merrill from the Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, on the basis of 804 patient-years of belimumab experience and 121 patient-years of placebo experience, the incidence (per 100 patient-years) of infections, adverse events, serious adverse events, and malignancies was comparable between the belimumab- and placebo-receiving patients.[6]

Two phase 3, multicenter, randomized, double-blind, placebo-controlled studies to evaluate the efficacy and safety of belimumab in lupus patients are in progress.[7,8]

Rituximab

Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes B cells, and it is FDA-approved for the treatment of rheumatoid arthritis. Although 2 multicenter, randomized, double-blind, controlled trials of B-cell depletion with rituximab are in progress for the treatment of active nonrenal SLE and active lupus nephritis[9,10] there were 5 open-label, uncontrolled studies (case series) presented at the 2007 ACR meeting demonstrating that rituximab can reduce lupus disease activity. It is important to keep in mind that these small case series discussed below are only descriptive and not powerful enough for definitive clinical conclusions.

Dr. Shirish Sangle from the Lupus Research Unit of the Rayne Institute, London, United Kingdom, presented data from 16 SLE patients resistant to conventional immunosuppressive therapy who received 2 doses of 1000 mg rituximab with IV CYC 500 mg and methylprednisolone 500 mg 2 weeks apart.[11] Overall, during the 4-6 months of follow-up, 9 of 16 patients (56%) had clinical improvement with a significant reduction in the British Isles Lupus Assessment Group (BILAG) scores. Of 12 patients with World Health Organization class III, IV, or V lupus nephritis, 5 patients with severe proliferative crescentic lupus nephritis failed to respond to the treatment.

Dr. Zahir Amoura from the Hospital Pitie Salpetriere, Paris, France, presented 22 SLE patients who received rituximab (375 mg/m2/week x 4, 750 mg at day 1 and 15, or 1000 mg at day 1 and 15) with or without other immunosuppressive agents for different lupus manifestations (the majority were lupus nephritis and hematologic manifestations); 18 of 22 patients (82%) had a favorable outcome assessed by the physician.[12] Of interest, all 13 patients with hematologic manifestations refractory to conventional immunosuppressive medications had improvement (eg, normal hemoglobin levels or platelet counts > 100 x 109/L), and 5 of 8 patients (63%) with lupus nephritis had more than a 50% decrease in proteinuria at 6 months.

Dr. Yoshiya Tanaka, from the University of Occupational and Environmental Health, Kitakyushu, Japan, presented long-term follow-up data from 19 refractory SLE patients who were treated with rituximab (375 mg/m2/week x 2) for lupus nephritis and/or neuropsychiatric lupus; 14 of 19 patients (74%) went into remission within 1-17 months of treatment.[13] Although the remission was sustained in 10 of 14 patients (71%) for more than 12 months, 5 of 10 patients (50%) relapsed after 7-23 months. Only 3 of 5 patients (60%) who relapsed received rituximab again, and two of them responded to retreatment.

Dr. Elisabeth Welin Henriksson, from the Karolinska Institute, Stockholm, Sweden, analyzed the health-related quality of life of 20 SLE patients resistant to conventional immunosuppressive therapy who received rituximab (375 mg/m2/week x 4), cyclophosphamide (500 mg/m2 x 2), and corticosteroids as part of an investigational protocol.[14] Following 6 months of treatment, the investigators demonstrated statistically significant improvements in the social functioning and vitality concepts of the 36-Item Short-Form Health Survey (SF-36), fatigue by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-fatigue) scale, and global health by visual analog scale. (These improvements were parallel to a significant decrease in SLEDAI scores.) However, there was no statistical improvement in the general health and mental health, physical function, usual role activities (because of physical health or emotional problems), and bodily pain concepts of the SF-36.

Dr. Renuka Basavaraju, from the Kansas University Medical Center, Kansas City, Kansas, presented their experience with rituximab (1000 mg 2 weeks apart) as an adjunct therapy to standard medications in 12 antiphospholipid syndrome (APS) patients (primary APS: 5 and SLE-associated APS: 7).[15] Although the use of other concomitant medications at the time of acute antiphospholipid (aPL)-related events is a major confounder that limits meaningful clinical conclusions, it was interesting to note that of 5 patients with high (> 80) pretreatment anticardiolipin (aCL) titers, 4 patients had no improvement in aCL titers and the remaining 1 patient was not tested after the rituximab infusion. Another pilot study of rituximab for anticoagulation-resistant manifestations of APS is in progress.[16]

Type I Interferon

Type I interferon (IFN) may play a major role in the pathogenesis of SLE; a correlation between IFN expression and lupus disease activity has been demonstrated. Dr. Daniel Wallace, from Cedars-Sinai/UCLA School of Medicine, Los Angeles, California, and Dr. Joan Merrill, from the Oklahoma Medical Research Foundation, presented the results of a double-blind, placebo-controlled (with 2:1 randomization), 84-day follow-up, phase 1, dose-escalation study of a single IV dose (with 5 different doses) of fully human anti-IFN-alfa monoclonal antibody (MEDI-545) injection in lupus patients.[17,18] The primary objective of this study was to determine the safety and tolerability of IFN-alfa in lupus patients, and there was no difference between IFN-alfa- and placebo-treated patients with respect to adverse or serious adverse events, including viral infections. Furthermore, there was dose-dependent inhibition of type I IFN-alfa-inducible genes in whole blood samples (an effect not shown by placebo), and this effect corresponded with the inhibition of type I IFN-alfa-inducible genes in skin samples. Clinical outcomes (eg, SELENA-SLEDAI scores or number of flares during the follow-up period) also significantly improved in 33 IFN-alfa-receiving lupus patients, compared with 17 placebo-receiving patients. Another multicenter, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study (with an open-label extension) to evaluate the safety and tolerability of multiple IV doses of IFN-alfa (MEDI-545) for active lupus patients is in progress.[19]

Conclusion

Given that there are many potential lupus medications undergoing phase 1, 2, and 3 trials, the future of lupus clinical research is very promising. Studies presented at the 2007 ACR meeting suggested that we may not have to wait another 30 years for new lupus medications.

This activity is supported by an independent educational grant from Abbott, Bristol-Myers Squibb, Forest, and Genentech.


References

References

  1. Ginzler EM, Appel GB, Dooley MA, et al. Mycophenolate Mofetil and Intravenous Cyclophosphamide in the Aspreva Lupus Management Study (ALMS): efficacy by racial group. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #L13]
  2. ClinicalTrials.gov. A study of CellCept (mycophenolate mofetil) in management of patients with lupus nephritis. Available at: http://clinicaltrials.gov/show/NCT00377637 Accessed December 20, 2007.
  3. ClinicalTrials.gov. mycophenolate mofetil versus azathioprine for maintenance therapy of lupus nephritis. Available at: http://clinicaltrials.gov/ct2/show/NCT00204022 Accessed December 20, 2007.
  4. Petri M, Furie R, Ginzler E, et al. Novel combined response endpoint and systemic lupus erythematosus (SLE) flare index (SFI) demonstrate belimumab (fully human monoclonal antibody to BLyS) improves or stabilizes SLE disease activity and reduces flare rate over 2.5 years of therapy. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #1316]
  5. Stohl W, Chatham W, McKay J, et al. Progressive normalization of autoantibody, immunoglobulin, and complement levels over 2.5 years of belimumab (fully human monoclonal antibody to BLyS) therapy in systemic lupus erythematosus (SLE) patients. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #426]
  6. Merrill JT, Wallace DJ, Stohl W, et al. Safety profile of belimumab (fully human monoclonal antibody to BLyS) in patients with systemic lupus erythematosus (SLE) treated during a placebo-controlled trial and in a long-term continuation study. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #427]
  7. ClinicalTrials.gov. A study of belimumab, a fully human monoclonal anti-BLyS antibody, in subjects with systemic lupus erythematosus (SLE). Available at: http://clinicaltrials.gov/show/NCT00410384 Accessed December 20, 2007.
  8. ClinicalTrials.gov. A study of belimumab, a fully human monoclonal anti-BLyS antibody, in subjects with systemic lupus erythematosus (SLE). Available at: http://clinicaltrials.gov/ct2/show/NCT00424476?cntry1=ES%3AKR Accessed December 20, 2007.
  9. ClinicalTrials.gov. A study to evaluate the efficacy and safety of rituximab in patients with severe systemic lupus erythematosus (EXPLORER). Available at: http://www.clinicaltrials.gov/ct/show/NCT00137969?order=14 Accessed December 20, 2007.
  10. ClinicalTrials.gov. A study to evaluate the efficacy and safety of rituximab in subjects with ISN/RPS class III or IV lupus nephritis (LUNAR). Available at: http://clinicaltrials.gov/show/NCT00282347 Accessed December 20, 2007.
  11. Sangle SR, Davies RJ, Aslam L, et al. Rituximab in the treatment of resistant systemic lupus erythematosus: failure of therapy in rapidly progressive crescentic lupus nephritis. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #441]
  12. Amoura Z, Mazodier K, Michel M, et al. Efficacy of rituximab in systemic lupus erythematosus: a series of 22 cases. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #1124]
  13. Tanaka Y, Tokunaga M, Nawata M, et al. Long-term follow up of rituximab (anti-CD20) therapy for refractory systemic lupus erythematosus. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #1939]
  14. Henriksson EW, Jonsdottir T, Gunnarsson I, van Vollenhoven RF. Reduced fatigue and improved self-perceived social function in patients with severe SLE treated with rituximab. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #2169]
  15. Basavaraju RV, Schue J, Latinis K, Stechschulte DJ. Rituximab an adjunct therapy for antiphospholipid syndrome: a study of twelve cases. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #F3]
  16. ClinicalTrials.gov. A pilot study of rituximab for the anticoagulation resistant manifestations of antiphospholipid syndrome (RITAPS). Available at: http://clinicaltrials.gov/show/NCT00537290 Accessed December 20, 2007.
  17. Wallace DJ, Petri M, Olsen N, et al. MEDI-545, an anti-interferon alpha monoclonal antibody, shows evidence of clinical activity in systemic lupus erythematosus. Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #1315]
  18. Merrill JT, Levin R, Chindalore V, et al. Safety of MEDI-545, an anti-interferon-alpha monoclonal antibody, in MI-CP126, a phase 1 study in systemic lupus erythematosus (SLE). Program and abstracts of the American College of Rheumatology (ACR) 71st Annual Meeting; November 6-11, 2007; Boston, Massachusetts. [Abstract #428]
  19. ClinicalTrials.gov. A study to evaluate the safety and tolerability of multiple IV doses of an antibody, in patients with systemic lupus erythematosus. Available at: http://clinicaltrials.gov/show/NCT00482989 Accessed December 20, 2007.