MOONLIGHT study: the design of a comparative study of the effectiveness of belimumab in patients with a history of lupus nephritis from the post-Marketed effectiveness of belimumab cOhOrt and JapaN Lupus NatIonwide reGistry (LUNA) coHorT

Kenei Sada, Noriaki Kurita, Hisashi Noma, Taizo Matsuki, Holly Quasny, Roger A Levy, Angela R Jones-Leone, Kerry Gairy, Nobuyuki Yajima, Kenei Sada, Noriaki Kurita, Hisashi Noma, Taizo Matsuki, Holly Quasny, Roger A Levy, Angela R Jones-Leone, Kerry Gairy, Nobuyuki Yajima

Abstract

Introduction: Lupus nephritis (LN) is more prevalent in patients with SLE of Asian ethnicity than in Caucasian patients. Belimumab became available in Japan in 2017 to treat patients with SLE, including those with LN. In the BLISS-LN trial (NCT01639339), belimumab showed a favourable effect on renal outcomes when combined with standard therapy (ST) starting at the induction treatment phase for active LN, but real-world effectiveness of belimumab in LN has not been extensively studied. Here we describe the protocol for the MOONLIGHT (post-Marketed effectiveness of belimumab cOhOrt and JapaN Lupus NatIonwide ReGistry (LUNA) coHorT) study, which will use data from a Japan postmarketing surveillance study and the Lupus Registry of Nationwide Institutions (LUNA) to evaluate the real-world effectiveness of belimumab plus ST versus ST alone in patients with a history of active LN who are not in the induction phase.

Methods and analysis: This multicentre, retrospective, observational study (GSK Study 214710) will enrol adults with SLE and a history of active LN, holding ≥3 years of complete follow-up data from the initiation of belimumab (no continuous treatment required). Data for patients with belimumab plus ST treatment (postmarketing registry data, belimumab cohort) will be compared with those for patients with ST only treatment (LUNA data, comparison cohort). Patients who discontinue/initiate belimumab after the start of the follow-up may be included in the comparison/belimumab cohort, respectively. The primary endpoint will be the occurrence of renal flares, for which belimumab's effectiveness will be estimated using a marginal structural model to consider time-dependent treatment and confounding factors. Secondary endpoints will include change in corticosteroid dose, renal disease activity, extrarenal disease activity, disease severity/activity biomarkers, LN class changes, end-stage kidney disease events and hospitalisations.

Ethics and dissemination: This study will be conducted according to the Declaration of Helsinki and the local ethical guidelines. Findings will be submitted to peer-reviewed journals and presented at scientific meetings.

Keywords: B-Lymphocytes; Biological Products; Lupus Nephritis; Therapeutics.

Conflict of interest statement

Competing interests: KS received speaker and consulting fees from GSK K.K. and a research grant from Pfizer. NK received a consulting fee from GSK K.K. HN received a consulting fee from GSK K.K. and personal fees from Boehringer Ingelheim, Kyowa Kirin, Toyota Motor Corporation, GSK, Ono Pharmaceutical, Sony and Terumo outside the submitted work. TM, HQ, RAL, ARJL and KG are employees of GSK and hold stocks and shares in the company. NY received a speaker’s fee from Pfizer.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
The study cohort and data collection scheme. Index date for belimumab cohort is defined as the date of belimumab initiation. For the comparison cohort, index date is defined as the day of 3 years prior to the last record in the LUNA registry. LUNA, Lupus Registry of Nationwide Institutions.

References

    1. Hanly JG, O'Keeffe AG, Su L, et al. . The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology 2016;55:252–62. 10.1093/rheumatology/kev311
    1. Almaani S, Meara A, Rovin BH. Update on lupus nephritis. Clin J Am Soc Nephrol 2017;12:825–35. 10.2215/CJN.05780616
    1. Seligman VA, Lum RF, Olson JL, et al. . Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med 2002;112:726–9. 10.1016/S0002-9343(02)01118-X
    1. Osio-Salido E, Manapat-Reyes H. Epidemiology of systemic lupus erythematosus in Asia. Lupus 2010;19:1365–73. 10.1177/0961203310374305
    1. Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015: a systematic review and Bayesian meta-analysis. Arthritis Rheumatol 2016;68:1432–41. 10.1002/art.39594
    1. Croca SC, Rodrigues T, Isenberg DA. Assessment of a lupus nephritis cohort over a 30-year period. Rheumatology 2011;50:1424–30. 10.1093/rheumatology/ker101
    1. Mahajan A, Amelio J, Gairy K, et al. . Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping disease severity and progression. Lupus 2020;29:1011–20. 10.1177/0961203320932219
    1. Parikh SV, Rovin BH. Current and emerging therapies for lupus nephritis. J Am Soc Nephrol 2016;27:2929–39. 10.1681/ASN.2016040415
    1. Tanaka Y, Mizukami A, Kobayashi A, et al. . Disease severity and economic burden in Japanese patients with systemic lupus erythematosus: a retrospective, observational study. Int J Rheum Dis 2018;21:1609–18. 10.1111/1756-185X.13363
    1. Yap DYH, Chan TM. Lupus nephritis in Asia: clinical features and management. Kidney Dis 2015;1:100–9. 10.1159/000430458
    1. Bruce IN, O'Keeffe AG, Farewell V, et al. . Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis 2015;74:1706–13. 10.1136/annrheumdis-2013-205171
    1. Thamer M, Hernán MA, Zhang Y, et al. . Prednisone, lupus activity, and permanent organ damage. J Rheumatol 2009;36:560–4. 10.3899/jrheum.080828
    1. Murimi-Worstell IB, Lin DH, Nab H, et al. . Association between organ damage and mortality in systemic lupus erythematosus: a systematic review and meta-analysis. BMJ Open 2020;10:e031850. 10.1136/bmjopen-2019-031850
    1. Baker KP, Edwards BM, Main SH, et al. . Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum 2003;48:3253–65. 10.1002/art.11299
    1. GlaxoSmithKline . Belimumab prescribing information. Available: [Accessed February 2022].
    1. Furie R, Petri M, Zamani O, et al. . A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918–30. 10.1002/art.30613
    1. Navarra SV, Guzmán RM, Gallacher AE, et al. . Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:721–31. 10.1016/S0140-6736(10)61354-2
    1. Zhang F, Bae S-C, Bass D, et al. . A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China, Japan and South Korea. Ann Rheum Dis 2018;77:355–63. 10.1136/annrheumdis-2017-211631
    1. Tanaka Y, Bae S-C, Bass D, et al. . Long-Term open-label continuation study of the safety and efficacy of belimumab for up to 7 years in patients with systemic lupus erythematosus from Japan and South Korea. RMD Open 2021;7. 10.1136/rmdopen-2021-001629
    1. Dooley MA, Houssiau F, Aranow C, et al. . Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus 2013;22:63–72. 10.1177/0961203312465781
    1. Furie R, Rovin BH, Houssiau F, et al. . Two-Year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 2020;383:1117–28. 10.1056/NEJMoa2001180
    1. Rovin BH, Furie R, Teng YKO, et al. . A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Kidney Int 2022;101:403–13. 10.1016/j.kint.2021.08.027
    1. Ohashi K, Sada K-E, Asano Y, et al. . Risk factors for chronic damage accumulation across different onset eras in systemic lupus erythematosus: a cross-sectional analysis of a Lupus Registry of Nationwide Institutions (LUNA). Acta Med Okayama 2020;74:191–8. 10.18926/AMO/59949
    1. Saito M, Yajima N, Yanai R, et al. . Prevalence and treatment conditions for hypertension and dyslipidaemia complicated with systemic lupus erythematosus: a multi-centre cross-sectional study. Lupus 2021;30:1146–53. 10.1177/09612033211006790
    1. Gladman D, Ginzler E, Goldsmith C, et al. . The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363–9. 10.1002/art.1780390303
    1. Morishita M, Sada K-E, Ohashi K, et al. . Damage accrual related to pregnancies before and after diagnosis of systemic lupus erythematosus: a cross-sectional and nested case-control analysis from a lupus registry. Lupus 2020;29:176–81. 10.1177/0961203319898766
    1. Aringer M, Costenbader K, Daikh D. European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019;2019:1400–12. 10.1002/art.40930
    1. Matsuo S, Imai E, Horio M, et al. . Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009;53:982–92. 10.1053/j.ajkd.2008.12.034
    1. Gordon C, Jayne D, Pusey C, et al. . European consensus statement on the terminology used in the management of lupus glomerulonephritis. Lupus 2009;18:257–63. 10.1177/0961203308100481
    1. Sprangers B, Monahan M, Appel GB. Diagnosis and treatment of lupus nephritis flares--an update. Nat Rev Nephrol 2012;8:709–17. 10.1038/nrneph.2012.220
    1. Robins JM, Hernán MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:550–60. 10.1097/00001648-200009000-00011
    1. Lertdumrongluk P, Streja E, Rhee CM, et al. . Dose of hemodialysis and survival: a marginal structural model analysis. Am J Nephrol 2014;39:383–91. 10.1159/000362285
    1. VanderWeele TJ. Marginal structural models for the estimation of direct and indirect effects. Epidemiology 2009;20:18–26. 10.1097/EDE.0b013e31818f69ce
    1. Cole SR, Hernán MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol 2008;168:656–64. 10.1093/aje/kwn164
    1. White IR, Royston P, Wood AM. Multiple imputation using chained equations: issues and guidance for practice. Stat Med 2011;30:377–99. 10.1002/sim.4067
    1. Parikh SV, Nagaraja HN, Hebert L, et al. . Renal flare as a predictor of incident and progressive CKD in patients with lupus nephritis. Clin J Am Soc Nephrol 2014;9:279–84. 10.2215/CJN.05040513
    1. Yap DYH, Tang C, Ma MKM, et al. . Longterm data on disease flares in patients with proliferative lupus nephritis in recent years. J Rheumatol 2017;44:1375–83. 10.3899/jrheum.170226
    1. Sahin GM, Sahin S, Kiziltas S, et al. . Mycophenolate mofetil versus azathioprine in the maintenance therapy of lupus nephritis. Ren Fail 2008;30:865–9. 10.1080/08860220802353843
    1. Mok CC, Ying KY, Ng WL, et al. . Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide. Am J Med 2006;119:355.e25–355.e33. 10.1016/j.amjmed.2005.08.045
    1. Joo YB, Kang YM, Kim H-A, et al. . Outcome and predictors of renal survival in patients with lupus nephritis: comparison between cyclophosphamide and mycophenolate mofetil. Int J Rheum Dis 2018;21:1031–9. 10.1111/1756-185X.13274
    1. Jakes RW, Bae S-C, Louthrenoo W, et al. . Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality. Arthritis Care Res 2012;64:159–68. 10.1002/acr.20683
    1. Dhir V, Aggarwal A, Lawrence A, et al. . Long-term outcome of lupus nephritis in Asian Indians. Arthritis Care Res 2012;64:713–20. 10.1002/acr.21597
    1. Houssiau FA, Vasconcelos C, D'Cruz D, et al. . The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010;69:61–4. 10.1136/ard.2008.102533
    1. Korbet SM, Schwartz MM, Evans J, et al. . Severe lupus nephritis: racial differences in presentation and outcome. J Am Soc Nephrol 2007;18:244–54. 10.1681/ASN.2006090992
    1. Yap DYH, Tang CSO, Ma MKM, et al. . Survival analysis and causes of mortality in patients with lupus nephritis. Nephrol Dial Transplant 2012;27:3248–54. 10.1093/ndt/gfs073
    1. Kono M, Yasuda S, Kato M, et al. . Long-term outcome in Japanese patients with lupus nephritis. Lupus 2014;23:1124–32. 10.1177/0961203314536246
    1. Chan TM, Tse KC, Tang CSO, et al. . Long-term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus 2005;14:265–72. 10.1191/0961203305lu2081oa
    1. Chan TM, Li FK, Tang CS, et al. . Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000;343:1156–62. 10.1056/NEJM200010193431604
    1. Ong LM, Hooi LS, Lim TO, et al. . Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology 2005;10:504–10. 10.1111/j.1440-1797.2005.00444.x
    1. Li X, Ren H, Zhang Q, et al. . Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 2012;27:1467–72. 10.1093/ndt/gfr484
    1. Hiromura K, Ikeuchi H, Kayakabe K, et al. . Clinical and histological features of lupus nephritis in Japan: a cross-sectional analysis of the Japan Renal Biopsy Registry (J-RBR). Nephrology 2017;22:885–91. 10.1111/nep.12863
    1. Jolly M, Toloza S, Goker B, et al. . Disease-specific quality of life in patients with lupus nephritis. Lupus 2018;27:257–64. 10.1177/0961203317717082
    1. Miyazaki C, Sruamsiri R, Mahlich J, et al. . Treatment patterns and medical cost of systemic lupus erythematosus patients in Japan: a retrospective claims database study. J Med Econ 2020;23:786–99. 10.1080/13696998.2020.1740236
    1. Fanouriakis A, Kostopoulou M, Alunno A, et al. . 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78:736–45. 10.1136/annrheumdis-2019-215089
    1. Gordon C, Amissah-Arthur M-B, Gayed M, et al. . The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology 2018;57:e1–45. 10.1093/rheumatology/kex286
    1. Japan College of Rheumatology . A treatment guideline for systemic lupus erythematosus 2019.
    1. Contreras G, Pardo V, Leclercq B, et al. . Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971–80. 10.1056/NEJMoa031855
    1. Bertsias GK, Tektonidou M, Amoura Z, et al. . Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71:1771–82. 10.1136/annrheumdis-2012-201940
    1. Ruperto N, Hanrahan LM, Alarcón GS, et al. . International consensus for a definition of disease flare in lupus. Lupus 2011;20:453–62. 10.1177/0961203310388445
    1. Miyazaki Y, Nakayamada S, Sonomoto K, et al. . Efficacy and safety of belimumab during maintenance therapy in patients with systemic lupus erythematosus. Rheumatology 2021. 10.1093/rheumatology/keab953. [Epub ahead of print: 28 Dec 2021].
    1. Stohl W, Schwarting A, Okada M, et al. . Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol 2017;69:1016–27. 10.1002/art.40049

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