Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of tacrolimus versus mycophenolate mofetil as induction treatment and low-dose tacrolimus as treatment for lupus nephritis: a meta-analysis

Wirksamkeit und Sicherheit von Tacrolimus vs. Mycophenolat-Mofetil als Induktionstherapie und niedrigdosiertem Tacrolimus zur Behandlung der Lupusnephritis: eine Metaanalyse

  • Originalien
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Abstract

Objective

The purpose of this study was to compare the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) as induction therapy and low-dose tacrolimus as treatment for lupus nephritis (LN).

Methods

Meta-analysis of randomized controlled trials (RCTs) was conducted to compare the efficacy and safety of tacrolimus and MMF as induction therapy for LN. We systematically reviewed RCTs and prospective cohort studies with a tacrolimus dose of 3 mg daily and performed a meta-analysis of the efficacy and safety of tacrolimus as an induction treatment for LN in comparison to MMF.

Results

The inclusion criteria were satisfied by eight studies (five RCTs and three prospective cohort studies) with a total of 408 individuals (289 for tacrolimus vs. MMF and 119 for low-dose tacrolimus). Tacrolimus and MMF had similar complete remission rates (odds ratio [OR] 1.028; 95% confidence interval [CI] 0.589–1.796; p = 0.922). The partial remission rate did not differ between the tacrolimus and MMF groups (OR 1.400; 95% CI 0.741–2.646; p = 0.300). Tacrolimus and MMF showed no differences in proteinuria, serum albumin, serum creatinine, creatinine clearance, renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), or extra-renal SLEDAI. The incidence of infection, severe infection, leukopenia, and hyperglycemia did not differ between the tacrolimus and MMF groups. However, herpes zoster infection was significantly less common in the tacrolimus group (OR 0.137; 95% CI 0.034–0.546; p = 0.005), whereas serum creatinine elevation was significantly higher in the tacrolimus group than in the MMF group (OR 8.148; 95% CI 1.369–48.50; p = 0.021). At 3 mg/d, tacrolimus was shown to be safe, well tolerated, and offered therapeutic benefits in all investigations.

Conclusion

Tacrolimus was comparable to MMF in terms of effectiveness and safety as an induction therapy for LN, with the exception of a reduced risk of herpes zoster infection and a rise in serum creatinine. In individuals with LN, 3 mg/d tacrolimus was proven to be efficacious and safe.

Zusammenfassung

Ziel

Ziel der Studie war es, die Wirksamkeit und Sicherheit von Tacrolimus und Mycophenolat-Mofetil (MMF) als Induktionstherapie und von niedrigdosiertem Tacrolimus zur Behandlung der Lupusnephritis (LN) zu untersuchen.

Methoden

Es wurde eine Metaanalyse randomisierter kontrollierter Studien (RCT) durchgeführt, um die Wirksamkeit und Sicherheit von Tacrolimus und Mycophenolat-Mofetil (MMF) als Induktionstherapie bei LN zu vergleichen. Dazu wurden RCT und prospektive Kohortenstudien mit einer täglichen Tacrolimusdosis von 3 mg systematisch überprüft und eine Metaanalyse der Wirksamkeit und Sicherheit von Tacrolimus als Induktionstherapie bei LN im Vergleich zu MMF durchgeführt.

Ergebnisse

Die Einschlusskriterien wurden von 8 Studien (5 RCT und 3 prospektive Kohortenstudien) mit insgesamt 408 Personen (289 für Tacrolimus vs. MMF und 119 für niedrigdosiertes Tacrolimus) erfüllt. Tacrolimus und MMF wiesen ähnliche komplette Remissionsraten auf (Odds Ratio [OR]: 1,028; 95%-Konfidenzintervall [95%-KCI]: 0,589–1,796; p = 0,922). Die partielle Remissionsrate unterschied sich nicht zwischen der Tacrolimus- und der MMF-Gruppe (OR: 1,400; 95%-KI: 0,741–2,646; p = 0,300). Bei Tacrolimus und MMF gab es keine Unterschiede in Bezug auf Proteinurie, Serumalbumin, Serumkreatinin, Kreatininclearance, den renalen Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) oder den extrarenalen SLEDAI. Auch die Inzidenz von Infektionen, schweren Infektionen, Leukopenien und Hyperglykämien unterschied sich nicht zwischen der Tacrolimus- und der MMF-Gruppe. Allerdings war eine Herpes-zoster-Infektion in der Tacrolimusgruppe signifikant weniger häufig (OR: 0,137; 95%-KI: 0,034–0,546; p = 0,005), während der Serumkreatininanstieg in der Tacrolimusgruppe signifikant höher war als in der MMF-Gruppe (OR: 8,148; 95%-KI: 1,369–48,50; p = 0,021). Bei Gabe von 3 mg/Tag erwies sich Tacrolimus als sicher und gut verträglich und bot in sämtlichen Untersuchungen therapeutische Vorteile.

Schlussfolgerung

Tacrolimus war in Bezug auf Wirksamkeit und Sicherheit als Induktionstherapie bei LN mit MMF vergleichbar, außer im Hinblick auf ein vermindertes Risiko für eine Herpes-zoster-Infektion und in Bezug auf einen Anstieg des Serumkreatinins. Bei Personen mit LN stellte sich Tacrolimus in der Dosis von 3 mg/Tag als wirksam und sicher heraus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lee Y, Choi S, Ji J, Song G (2016) Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis. Lupus 25(7):727–734

    Article  CAS  PubMed  Google Scholar 

  2. Almaani S, Meara A, Rovin BH (2017) Update on lupus nephritis. Clin J Am Soc Nephrol 12(5):825–835

    Article  PubMed  Google Scholar 

  3. Choi SJ, Ahn SM, Oh JS, Hong S, Lee C‑K, Yoo B et al (2022) Initial preserved renal function as a predictor of favorable renal response to rituximab in refractory or relapsing lupus nephritis: a single-center cohort study in korea. J Rheum Dis 29(1):22–32

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tektonidou MG, Dasgupta A, Ward MM (2016) Risk of end-stage renal disease in patients with lupus nephritis, 1971–2015: a systematic review and Bayesian meta-analysis. Arthritis Rheumatol 68(6):1432–1441

    Article  PubMed  PubMed Central  Google Scholar 

  5. Petri M (2004) Cyclophosphamide: new approaches for systemic lupus erythematosus. Lupus 13(5):366–371

    Article  CAS  PubMed  Google Scholar 

  6. Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R et al (2005) Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology 10(5):504–510

    Article  CAS  PubMed  Google Scholar 

  7. Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T et al (1987) FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40(9):1256–1265

    Article  CAS  PubMed  Google Scholar 

  8. Yoo W‑H, Lee S‑I, Kim T‑H, Sung J‑J, Kim SM, Hua F et al (2021) Safety of tacrolimus in autoimmune disease: results from post-marketing surveillance in south korea. J Rheum Dis 28(4):202–215

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jiang Y‑P, Zhao X‑X, Chen R‑R, Xu Z‑H, Wen C‑P, Yu J (2020) Comparative efficacy and safety of mycophenolate mofetil and cyclophosphamide in the induction treatment of lupus nephritis: a systematic review and meta-analysis. Medicine 99(38):e22328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou T, Lin S, Yang S, Lin W (2019) Efficacy and safety of tacrolimus in induction therapy of patients with lupus nephritis. Drug Des Devel Ther 13:857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee YH, Lee HS, Choi SJ, Ji JD, Song GG (2012) Associations between TLR polymorphisms and systemic lupus erythematosus: a systematic review and meta-analysis. Clin Exp Rheumatol 30(2):262–265

    PubMed  Google Scholar 

  12. Lee YH (2018) An overview of meta-analysis for clinicians. Korean J Intern Med 33(2):277–283

    Article  PubMed  Google Scholar 

  13. Lee YH (2019) Strengths and limitations of meta-analysis. Korean J Med 94(5):391–395

    Article  Google Scholar 

  14. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12

    Article  CAS  PubMed  Google Scholar 

  15. Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M et al (2000) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

    Google Scholar 

  16. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269

    Article  PubMed  Google Scholar 

  17. Davey Smith G, Egger M (1997) Meta-analyses of randomised controlled trials. Lancet 350(9085):1182

    Article  CAS  PubMed  Google Scholar 

  18. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    Article  PubMed  Google Scholar 

  19. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Miyasaka N, Kawai S, Hashimoto H (2009) Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. Mod Rheumatol 19(6):606–615

    Article  CAS  PubMed  Google Scholar 

  21. Tanaka H, Oki E, Tsuruga K, Yashiro T, Hanada I, Ito E (2009) Management of young patients with lupus nephritis using tacrolimus administered as a single daily dose. Clin Nephrol 72(6):430–436

    CAS  PubMed  Google Scholar 

  22. Li X, Ren H, Zhang Q, Zhang W, Wu X, Xu Y et al (2012) Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 27(4):1467–1472

    Article  CAS  PubMed  Google Scholar 

  23. Tanaka H, Watanabe S, Aizawa-Yashiro T, Oki E, Kumagai N, Tsuruga K et al (2012) Long-term tacrolimus-based immunosuppressive treatment for young patients with lupus nephritis: a prospective study in daily clinical practice. Nephron Clin Pract 121(3-4):c165–c73

    Article  CAS  PubMed  Google Scholar 

  24. Yap DY, Yu X, Chen XM, Lu F, Chen N, Li XW et al (2012) Pilot 24 month study to compare mycophenolate mofetil and tacrolimus in the treatment of membranous lupus nephritis with nephrotic syndrome. Nephrology 17(4):352–357

    Article  CAS  PubMed  Google Scholar 

  25. Fei Y, Wu Q, Zhang W, Chen H, Hou Y, Xu D et al (2013) Low-dose tacrolimus in treating lupus nephritis refractory to cyclophosphamide: a prospective cohort study. Clin Exp Rheumatol 31(1):62–68

    PubMed  Google Scholar 

  26. Mok CC, Ying KY, Yim CW, Siu YP, Tong KH, To CH et al (2016) Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis 75(1):30–36

    Article  PubMed  Google Scholar 

  27. Kamanamool N, Ingsathit A, Rattanasiri S, Ngamjanyaporn P, Kasitanont N, Chawanasuntorapoj R et al (2018) Comparison of disease activity between tacrolimus and mycophenolate mofetil in lupus nephritis: a randomized controlled trial. Lupus 27(4):647–656

    Article  CAS  PubMed  Google Scholar 

  28. Shin J‑M, Kim D, Kwon Y‑C, Ahn G‑Y, Lee J, Park Y et al (2021) Clinical and genetic risk factors associated with the presence of lupus nephritis. J Rheum Dis 28(3):150–158

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mok CC, Ho LY, Ying SKY, Leung MC, To CH, Ng WL (2020) Long-term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis. Ann Rheum Dis 79(8):1070–1076

    Article  PubMed  Google Scholar 

  30. Yang T‑H, Tsai-Hung W, Chang Y‑L, Liao H‑T, Chia-Chen H, Tsai C‑Y et al (2018) Cyclosporine for the treatment of lupus nephritis in patients with systemic lupus erythematosus. Clin Nephrol 89(4):277

    Article  PubMed  Google Scholar 

  31. Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z et al (2015) Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 162(1):18–26

    Article  PubMed  Google Scholar 

  32. Lee YH, Song GG (2022) Multitarget therapy versus monotherapy as induction treatment for lupus nephritis: a meta-analysis of randomized controlled trials. Lupus 31(12):1468–1476

    Article  CAS  PubMed  Google Scholar 

  33. Hannah J, Casian A, D’Cruz D (2016) Tacrolimus use in lupus nephritis: a systematic review and meta-analysis. Autoimmun Rev 15(1):93–101

    Article  CAS  PubMed  Google Scholar 

  34. Lee YH, Song GG (2020) Association between signal transducers and activators of transcription 4 rs7574865 polymorphism and systemic lupus erythematosus: a meta-analysis. J Rheum Dis 27(4):277–284

    Article  Google Scholar 

  35. Lee YH, Song GG (2020) Circulating interleukin-37 levels in rheumatoid arthritis and systemic lupus erythematosus and their correlations with disease activity: a meta-analysis. J Rheum Dis 27(3):152–158

    Article  Google Scholar 

  36. Lee YH, Song GG (2020) Circulating interleukin-18 level in systemic lupus erythematosus. J Rheum Dis 27(2):110–115

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seoul 02841, Seongbuk-gu, Korea (Republic of)

    Young Ho Lee MD PhD & Gwan Gyu Song

Authors
  1. Young Ho Lee MD PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gwan Gyu Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young Ho Lee MD PhD.

Ethics declarations

Conflict of interest

Y.H. Lee and G.G. Song declare that they have no competing interests.

For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.

Additional information

Redaktion

Ulf Müller-Ladner, Bad Nauheim

Uwe Lange, Bad Nauheim

Data Availability

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

figure qr

Scan QR code & read article online

Supplementary Information

393_2022_1313_MOESM1_ESM.pdf

Table S1. Characteristics of individual studies included in the meta-analysis of induction therapies for lupus nephritis. Table S2. Characteristics of the studies included in this systematic review of low-dose tacrolimus therapy in lupus nephritis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, Y.H., Song, G.G. Efficacy and safety of tacrolimus versus mycophenolate mofetil as induction treatment and low-dose tacrolimus as treatment for lupus nephritis: a meta-analysis. Z Rheumatol 82, 754–762 (2023). https://doi.org/10.1007/s00393-022-01313-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-022-01313-2

Keywords

Schlüsselwörter

Search

Navigation