Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Treat-to-target in systemic lupus erythematosus: advancing towards its implementation

Nature Reviews Rheumatology volume 18, pages 146–157 (2022)Cite this article

Subjects

This article has been updated

Abstract

The treat-to-target (T2T) concept has improved outcomes for patients with diabetes, hypertension and rheumatoid arthritis. This therapeutic strategy involves choosing a well-defined, relevant target, taking therapeutic steps, evaluating whether the target has been achieved, and taking action if it has not. The T2T principle has been embraced by systemic lupus erythematosus (SLE) experts, but measurable and achievable outcomes, and therapeutic options, are needed to make this approach possible in practice. Considerable evidence has been generated regarding meaningful ‘state’ outcomes for SLE. Low disease activity has been defined and studied, and the most aspirational goal, remission, has been defined by the Definition of Remission in SLE task force. By contrast, current therapeutic options in SLE are limited, and more effective and safer therapies are urgently needed. Fortunately, clinical trial activity in SLE has been unprecedented, and encouraging results have been seen for novel therapies, including biologic and small-molecule agents. Thus, with the expected advent of such treatments, it is likely that sufficiently diverse therapies for SLE will be available in the foreseeable future, allowing the routine implementation of T2T approaches in the care of patients with SLE.

Key points

  • The treat-to-target (T2T) therapeutic strategy consists of four key steps: establish a relevant individualized target, take steps to achieve it, monitor the target achievement, and adjust the therapy if the target is not achieved.

  • Validation of the Lupus Low Disease Activity State (LLDAS) definition of low disease activity and recent consensus on the final DORIS definition of remission in systemic lupus erythematosus (SLE) have provided feasible treatment targets for the adoption of a T2T strategy in SLE.

  • With the advent of novel therapeutics for SLE, including biologics and small molecules, T2T for SLE will become a clinical reality in the coming years.

  • The use of LLDAS and DORIS definitions in clinical trials for novel therapeutics could provide robust, discriminatory outcome measures.

  • Trials comparing the active attainment of LLDAS or DORIS remission as end points in a T2T approach with a conventional management approach are still needed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Treat-to-target therapeutic strategy for treatment of systemic lupus erythematosus.
Fig. 2: Proposed designs of T2T-based randomized controlled trials of novel therapies in SLE.

Similar content being viewed by others

Change history

  • 11 February 2022

    The formatting of Agner R. Parra Sánchez’s name in the xml was incorrect, resulting in Parra being wrongly classed as a middle name. This has now been corrected online.

References

  1. Atar, D., Birkeland, K. I. & Uhlig, T. ‘Treat to target’: moving targets from hypertension, hyperlipidaemia and diabetes to rheumatoid arthritis. Ann. Rheum. Dis. 69, 629–630 (2010).

    PubMed  Google Scholar 

  2. Wangnoo, S. K. et al. Treat-to-target trials in diabetes. Indian J. Endocrinol. Metab. 18, 166–174 (2014).

    PubMed  PubMed Central  Google Scholar 

  3. Castrejon, I. & Pincus, T. Differences in treat-to-target in patients with rheumatoid arthritis versus hypertension and diabetes — consequences for clinical care. Bull. NYU Hosp. Jt. Dis. 69, 104–110 (2011).

    PubMed  Google Scholar 

  4. Drosos, A. A., Pelechas, E. & Voulgari, P. V. Treatment strategies are more important than drugs in the management of rheumatoid arthritis. Clin. Rheumatol. 39, 1363–1368 (2020).

    PubMed  Google Scholar 

  5. Smolen, J. S. Treat to target in rheumatology: a historical account on occasion of the 10th anniversary. Rheum. Dis. Clin. North Am. 45, 477–485 (2019).

    PubMed  Google Scholar 

  6. Grigor, C. et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 364, 263–269 (2004).

    PubMed  Google Scholar 

  7. Aletaha, D., Alasti, F. & Smolen, J. S. Optimisation of a treat-to-target approach in rheumatoid arthritis: strategies for the 3-month time point. Ann. Rheum. Dis. 75, 1479–1485 (2016).

    PubMed  Google Scholar 

  8. Mueller, R. B. et al. Superiority of a treat-to-target strategy over conventional treatment with fixed csDMARD and corticosteroids: a multi-center randomized controlled trial in RA patients with an inadequate response to conventional synthetic DMARDs, and new therapy with certolizumab pegol. J. Clin. Med. 8, 302 (2019).

    CAS  PubMed Central  Google Scholar 

  9. Solomon, D. H. et al. Benefits and sustainability of a learning collaborative for implementation of treat-to-target in rheumatoid arthritis: results of a cluster-randomized controlled phase II clinical trial. Arthritis Care Res. 70, 1551–1556 (2018).

    Google Scholar 

  10. Goekoop-Ruiterman, Y. P. et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann. Intern. Med. 146, 406–415 (2007).

    PubMed  Google Scholar 

  11. Goekoop-Ruiterman, Y. P. et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 52, 3381–339 (2005).

    CAS  PubMed  Google Scholar 

  12. Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann. Rheum. Dis. 76, 960–977 (2017).

    PubMed  Google Scholar 

  13. Stoffer, M. A. et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update. Ann. Rheum. Dis. 75, 16–22 (2016).

    PubMed  Google Scholar 

  14. Dures, E. et al. Treat-to-target in PsA: methods and necessity. RMD Open 6, e001083 (2020).

    PubMed  PubMed Central  Google Scholar 

  15. Kiltz, U. et al. Treat-to-target (T2T) recommendations for gout. Ann. Rheum. Dis. 76, 632–638 (2017).

    CAS  PubMed  Google Scholar 

  16. Franklyn, K., Hoi, A., Nikpour, M. & Morand, E. F. The need to define treatment goals for systemic lupus erythematosus. Nat. Rev. Rheumatol. 10, 567–571 (2014).

    CAS  PubMed  Google Scholar 

  17. van Vollenhoven, R. F. et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann. Rheum. Dis. 73, 958–967 (2014).

    PubMed  Google Scholar 

  18. Franklyn, K. et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann. Rheum. Dis. 75, 1615–1621 (2016).

    CAS  PubMed  Google Scholar 

  19. van Vollenhoven, R. et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann. Rheum. Dis. 76, 554–561 (2017).

    PubMed  Google Scholar 

  20. Fanouriakis, A. et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann. Rheum. Dis. 78, 736–745 (2019).

    CAS  PubMed  Google Scholar 

  21. Piga, M. et al. Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus. Arthritis Res. Ther. 19, 247 (2017).

    PubMed  PubMed Central  Google Scholar 

  22. Hao, Y. et al. Determinants and protective associations of the lupus low disease activity state in a prospective Chinese cohort. Clin. Rheumatol. https://doi.org/10.1007/s10067-021-05940-z (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tsang, A. S. M. W. & Bultink, I. E. Systemic lupus erythematosus: review of synthetic drugs. Expert Opin. Pharmacother. 16, 2793–2806 (2015).

    Google Scholar 

  24. Basta, F., Fasola, F., Triantafyllias, K. & Schwarting, A. Systemic lupus erythematosus (SLE) therapy: the old and the new. Rheumatol. Ther. 7, 433–446 (2020).

    PubMed  PubMed Central  Google Scholar 

  25. Bruce, I. N. 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. 74, 1706–1713 (2015).

    CAS  PubMed  Google Scholar 

  26. Antonis Fanouriakis, G. B. Treat-to-target in lupus: what does the future hold? Int. J. Clin. Rheumatol. 10, 461–477 (2015).

    Google Scholar 

  27. Gatto, M., Zen, M., Iaccarino, L. & Doria, A. New therapeutic strategies in systemic lupus erythematosus management. Nat. Rev. Rheumatol. 15, 30–48 (2019).

    CAS  PubMed  Google Scholar 

  28. Aringer, M., Leuchten, N. & Schneider, M. Treat to target in systemic lupus erythematosus. Rheum. Dis. Clin. North Am. 45, 537–548 (2019).

    PubMed  Google Scholar 

  29. Golder, V. et al. Does expert opinion match the operational definition of the Lupus Low Disease Activity State (LLDAS)? A case-based construct validity study. Semin. Arthritis Rheum. 46, 798–803 (2017).

    PubMed  Google Scholar 

  30. Golder, V. E. A. Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. Lancet Rheumatol. 1, e95–e102 (2019).

    Google Scholar 

  31. Golder, V. et al. Association of the lupus low disease activity state (LLDAS) with health-related quality of life in a multinational prospective study. Arthritis Res. Ther. 19, 62 (2017).

    PubMed  PubMed Central  Google Scholar 

  32. Golder, V. et al. Frequency and predictors of the lupus low disease activity state in a multi-national and multi-ethnic cohort. Arthritis Res. Ther. 18, 260 (2016).

    PubMed  PubMed Central  Google Scholar 

  33. Babaoglu, H., Li, J., Goldman, D., Magder, L. S. & Petri, M. Time to lupus low disease activity state in the Hopkins Lupus Cohort: role of African American ethnicity. Arthritis Care Res. 72, 225–232 (2020).

    CAS  Google Scholar 

  34. van Vollenhoven, R. F. et al. 2021 DORIS definition of remission in SLE: final recommendations from an international task force. Lupus Sci. Med. 8, e000538 (2021).

    PubMed  PubMed Central  Google Scholar 

  35. Mucke, J., Dusing, C., Klose, N., Schneider, M. & Chehab, G. Remission in SLE — do DORIS criteria match the treating physician’s judgment? A cross sectional study to assess reasons for discordance. Rheumatology 60, 4298–4305 (2021).

    PubMed  Google Scholar 

  36. Petri, M. & Magder, L. S. Comparison of remission and lupus low disease activity state in damage prevention in a United States systemic lupus erythematosus cohort. Arthritis Rheumatol. 70, 1790–1795 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Zen, M. et al. The effect of different durations of remission on damage accrual: results from a prospective monocentric cohort of Caucasian patients. Ann. Rheum. Dis. 76, 562–565 (2017).

    PubMed  Google Scholar 

  38. Zen, M. et al. Prolonged remission in Caucasian patients with SLE: prevalence and outcomes. Ann. Rheum. Dis. 74, 2117–2122 (2015).

    CAS  PubMed  Google Scholar 

  39. Ugarte-Gil, M. F. et al. Remission and Low Disease Activity Status (LDAS) protect lupus patients from damage occurrence: data from a multiethnic, multinational Latin American Lupus Cohort (GLADEL). Ann. Rheum. Dis. 76, 2071–2074 (2017).

    PubMed  Google Scholar 

  40. Pons-Estel, G. et al. Impact of remission and low disease activity status on hospitalizations among SLE patients from the GLADEL Latin American Cohort [abstract]. Arthritis Rheumatol. 72, 1272 (2020).

    Google Scholar 

  41. Reategui-Sokolova, C. et al. Remission and low disease activity state prevent hospitalizations in systemic lupus erythematosus patients. Lupus 28, 1344–1349 (2019).

    CAS  PubMed  Google Scholar 

  42. Ugarte-Gil, M. et al. LLDAS (Low Lupus Disease Activity State) and remission prevent damage accrual in systemic lupus erythematosus (SLE) patients in a primarily Mestizo cohort [abstract]. Arthritis Rheumatol. 72, 0254 (2020).

    Google Scholar 

  43. Ugarte-Gil, M. F. et al. Better health-related quality of life in systemic lupus erythematosus predicted by low disease activity state/remission: data from the Peruvian Almenara Lupus Cohort. Arthritis Care Res. 72, 1159–1162 (2020).

    CAS  Google Scholar 

  44. Wilhelm, T. R., Magder, L. S. & Petri, M. Remission in systemic lupus erythematosus: durable remission is rare. Ann. Rheum. Dis. 76, 547–553 (2017).

    PubMed  Google Scholar 

  45. Tsang, A. S. M. W., Bultink, I. E., Heslinga, M. & Voskuyl, A. E. Both prolonged remission and Lupus Low Disease Activity State are associated with reduced damage accrual in systemic lupus erythematosus. Rheumatology 56, 121–128 (2017).

    Google Scholar 

  46. Tsang, A. S. M. W. P. et al. The relationship between remission and health-related quality of life in a cohort of SLE patients. Rheumatology 58, 628–635 (2019).

    Google Scholar 

  47. Golder, V. et al. Evaluation of remission definitions for systemic lupus erythematosus: a prospective cohort study. Lancet Rheumatol. 1, e103–e110 (2019).

    Google Scholar 

  48. Zirkzee, E., Bonte-Mineur, F. & Kok, M. Implementation of treat-to-target principles in the management of systemic lupus erythematosus. Lupus 27, 1218–1219 (2018).

    CAS  PubMed  Google Scholar 

  49. Bombardier, C., Gladman, D. D., Urowitz, M. B., Caron, D. & Chang, C. H. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 35, 630–640 (1992).

    CAS  PubMed  Google Scholar 

  50. Gladman, D. 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. 39, 363–369 (1996).

    CAS  PubMed  Google Scholar 

  51. Zandbelt, M. M., Welsing, P. M., van Gestel, A. M. & van Riel, P. L. Health Assessment Questionnaire modifications: is standardisation needed? Ann. Rheum. Dis. 60, 841–845 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Mucke, J., Kuss, O., Brinks, R., Schanze, S. & Schneider, M. LUPUS-BEST — treat-to-target in systemic lupus erythematosus: study protocol for a three-armed cluster-randomised trial. Lupus Sci. Med. 8, e000516 (2021).

    PubMed  PubMed Central  Google Scholar 

  53. Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

    CAS  PubMed  Google Scholar 

  54. Furie, R. 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. 63, 3918–3930 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Oon, S. et al. Lupus Low Disease Activity State (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus. Ann. Rheum. Dis. 78, 629–633 (2019).

    CAS  PubMed  Google Scholar 

  56. Parodis, I. et al. Predictors of low disease activity and clinical remission following belimumab treatment in systemic lupus erythematosus. Rheumatology 58, 2170–2176 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Parodis, I. et al. Definitions of remission in systemic lupus erythematosus: a post-hoc analysis of two randomised clinical trials. Lancet Rheumatol. 1, e163–e173 (2019).

    Google Scholar 

  58. Morand, E. F. et al. Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study. Rheumatology 59, 2930–2938 (2020).

    PubMed  PubMed Central  Google Scholar 

  59. Morand, E. F., Trasieva, T., Berglind, A., Illei, G. G. & Tummala, R. Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hoc analysis of the Phase IIb MUSE trial of anifrolumab. Ann. Rheum. Dis. 77, 706–713 (2018).

    CAS  PubMed  Google Scholar 

  60. Wallace, D. J. et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 392, 222–231 (2018).

    CAS  PubMed  Google Scholar 

  61. Doria, A. et al. Efficacy and safety of subcutaneous belimumab in anti-double-stranded DNA-positive, hypocomplementemic patients with systemic lupus erythematosus. Arthritis Rheumatol. 70, 1256–1264 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Stohl, W. et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 69, 1016–1027 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Furie, R. et al. Op0164 BLISS-LN: a randomised, double-blind, placebo-controlled phase 3 trial of intravenous belimumab in patients with active lupus nephritis. Ann. Rheum. Dis. 79, 103–103 (2020).

    Google Scholar 

  64. Merrill, J. T. et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62, 222–233 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Rovin, B. H. et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 64, 1215–1226 (2012).

    CAS  PubMed  Google Scholar 

  66. Ryden-Aulin, M. et al. Off-label use of rituximab for systemic lupus erythematosus in Europe. Lupus Sci. Med. 3, e000163 (2016).

    PubMed  PubMed Central  Google Scholar 

  67. Furie R. et al. Two-year results from a randomized, controlled study of obinutuzumab for proliferative lupus nephritis [abstract]. Arthritis Rheumatol. https://acrabstracts.org/abstract/two-year-results-from-a-randomized-controlled-study-of-obinutuzumab-for-proliferative-lupus-nephritis/ (2020).

  68. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04221477 (2021).

  69. Lavie, F. et al. Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production. Ann. Rheum. Dis. 66, 700–703 (2007).

    CAS  PubMed  Google Scholar 

  70. Kraaij, T. et al. Long-term effects of combined B-cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrol. Dial. Transpl. 36, 1474–1483 (2020).

    Google Scholar 

  71. Shipa, M. et al. OP0129 Belimumab after rituximab significantly reduced IgG anti-dsDNA antibody levels and prolonged time to severe flare in patients with systemic lupus erythematosus [abstract]. Ann. Rheum. Dis. 80, 74–74 (2021).

    Google Scholar 

  72. Teng, Y. K. O. et al. Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. BMJ Open 9, e025687 (2019).

    PubMed  PubMed Central  Google Scholar 

  73. Carreira, P. L. & Isenberg, D. A. Recent developments in biologic therapies for the treatment of patients with systemic lupus erythematosus. Rheumatology 58, 382–387 (2019).

    CAS  PubMed  Google Scholar 

  74. Furie, R. et al. Efficacy and safety of dapirolizumab pegol in patients with moderately to severely active systemic lupus erythematosus: a randomized, placebo-controlled study [abstract]. Arthritis Rheumatol. 71, 944 (2019).

    Google Scholar 

  75. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04294667 (2021).

  76. Reynolds, J. A. et al. Cytokine profiling in active and quiescent SLE reveals distinct patient subpopulations. Arthritis Res. Ther. 20, 173 (2018).

    PubMed  PubMed Central  Google Scholar 

  77. Rovin, B. H. et al. A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of treatment with sirukumab (CNTO 136) in patients with active lupus nephritis. Arthritis Rheumatol. 68, 2174–2183 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542–552 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. van Vollenhoven, R. F. et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 392, 1330–1339 (2018).

    PubMed  Google Scholar 

  80. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03517722 (2021).

  81. Mullard, A. FDA approves AstraZeneca’s anifrolumab for lupus. Nat. Rev. Drug Discov. 20, 658 (2021).

    PubMed  Google Scholar 

  82. Furie, R. et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 69, 376–386 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Furie, R. A. et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 1, e208–e219 (2019).

    Google Scholar 

  84. Morand, E. F. et al. Trial of anifrolumab in active systemic lupus erythematosus. N. Engl. J. Med. 382, 211–221 (2020).

    CAS  PubMed  Google Scholar 

  85. Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). Protocole d’utilisation therapeutique et de recueil d’informations Anifrolumab 300 mg, solution à diluer pour perfusion. ATU de Cohorte. https://ansm.sante.fr/uploads/2021/07/23/20210723-atuc-anifrolumab-put.pdf (2021).

  86. Ishii, T. et al. Multicenter double-blind randomized controlled trial to evaluate the effectiveness and safety of bortezomib as a treatment for refractory systemic lupus erythematosus. Mod. Rheumatol. 28, 986–992 (2018).

    CAS  PubMed  Google Scholar 

  87. Walhelm, T. et al. Clinical experience of proteasome inhibitor bortezomib regarding efficacy and safety in severe systemic lupus erythematosus: a nationwide study. Front. Immunol. 12, 756941 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Aringer, M. Janus kinase inhibitors clear to land. Rheumatology 57, 1131–1132 (2018).

    CAS  PubMed  Google Scholar 

  89. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03843125 (2021).

  90. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03616964 (2021).

  91. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03616912 (2021).

  92. Singhal, S. et al. 5 Oral selective tyrosine kinase 2 (TYK2) inhibition with BMS-986165 in patients with systemic lupus erythematosus: a phase 2, randomized, double-blind, placebo-controlled study (PAISLEY) [abstract]. Lupus Sci. Med. 6, A5–A6 (2019).

    Google Scholar 

  93. Shao, W. H. & Cohen, P. L. The role of tyrosine kinases in systemic lupus erythematosus and their potential as therapeutic targets. Expert Rev. Clin. Immunol. 10, 573–582 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04305197 (2021).

  95. Rovin, B. H. et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. 95, 219–231 (2019).

    CAS  PubMed  Google Scholar 

  96. Onno Teng, Y. K., Parikh, S. V., Saxena, A., Solomons, N. & Huizinga, R. B. AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (LN) [abstract]. Lupus Sci. Med. 7, 011 (2020).

    Google Scholar 

  97. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03021499 (2021).

  98. Merrill, J. T. et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb Study. Arthritis Rheumatol. 70, 266–276 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Merrill, J. T. et al. Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 77, 883–889 (2018).

    CAS  PubMed  Google Scholar 

  100. Merrill, J. T. et al. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann. Rheum. Dis. 75, 332–340 (2016).

    CAS  PubMed  Google Scholar 

  101. Cogollo, E., Silva, M. A. & Isenberg, D. Profile of atacicept and its potential in the treatment of systemic lupus erythematosus. Drug Des. Devel. Ther. 9, 1331–1339 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Ginzler, E. M. et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res. Ther. 14, R33 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02885610 (2020).

  104. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04082416 (2021).

  105. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03312907 (2021).

  106. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT00539838 (2020).

  107. Mysler, E. F. et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum. 65, 2368–2379 (2013).

    CAS  PubMed  Google Scholar 

  108. Clowse, M. E. et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: results from two phase III randomized, double-blind, placebo-controlled trials. Arthritis Rheumatol. 69, 362–375 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Merrill, J. T. et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 62, 3077–3087 (2010).

    CAS  PubMed  Google Scholar 

  110. Furie, R. et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol. 66, 379–389 (2014).

    CAS  PubMed  Google Scholar 

  111. Pimentel-Quiroz, V. R., Ugarte-Gil, M. F. & Alarcon, G. S. Abatacept for the treatment of systemic lupus erythematosus. Expert Opin. Investig. Drugs 25, 493–499 (2016).

    CAS  PubMed  Google Scholar 

  112. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04181762 (2021).

  113. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04376827 (2021).

  114. Jayne, D. et al. POS0690 Randomized, controlled, phase 2 trial of type 1 IFN inhibitor anifrolumab in patients with active proliferative lupus nephritis. Ann. Rheum. Dis. 80, 592–592 (2021).

    Google Scholar 

  115. Werth, V. et al. OP0193 BIIB059, a humanized monoclonal antibody targeting BDCA2 on plasmacytoid dendritic cells (pDC), shows dose-related efficacy in the phase 2 LILAC study in patients (pts) with active cutaneous lupus erythematosus (CLE). Ann. Rheum. Dis. 79, 120–121 (2020).

    Google Scholar 

  116. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02847598 (2020).

  117. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04895241 (2021).

  118. Hasni, S. et al. 183 A phase 1B/2A trial of tofacitinib, an oral Janus kinase inhibitor, in systemic lupus erythematosus [abstract]. Lupus Sci. Med. 6, A139–A140 (2019).

    Google Scholar 

  119. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03159936 (2020).

  120. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03288324 (2021).

  121. US National library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02908100 (2020).

  122. Hanly, J. G. et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology 55, 252–262 (2016).

    PubMed  Google Scholar 

  123. Wang, H., Ren, Y. L., Chang, J., Gu, L. & Sun, L. Y. A systematic review and meta-analysis of prevalence of biopsy-proven lupus nephritis. Arch. Rheumatol. 33, 17–25 (2018).

    PubMed  Google Scholar 

  124. Fanouriakis, A. et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann. Rheum. Dis. 79, 713–723 (2020).

    CAS  PubMed  Google Scholar 

  125. Kostopoulou, M., Adamichou, C. & Bertsias, G. An update on the diagnosis and management of lupus nephritis. Curr. Rheumatol. Rep. 22, 30 (2020).

    PubMed  Google Scholar 

  126. Zeher, M. et al. Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis. Lupus 20, 1484–1493 (2011).

    CAS  PubMed  Google Scholar 

  127. Condon, M. B. et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann. Rheum. Dis. 72, 1280–1286 (2013).

    CAS  PubMed  Google Scholar 

  128. Davidson, J. E. et al. Renal remission status and longterm renal survival in patients with lupus nephritis: a retrospective cohort analysis. J. Rheumatol. 45, 671–677 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Dall’Era, M. et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort. Arthritis Rheumatol. 67, 1305–1313 (2015).

    PubMed  Google Scholar 

  130. Tamirou, F. et al. A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial. Lupus Sci. Med. 2, e000123 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. Ugolini-Lopes, M. R. et al. Early proteinuria response: a valid real-life situation predictor of long-term lupus renal outcome in an ethnically diverse group with severe biopsy-proven nephritis? Lupus Sci. Med. 4, e000213 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. Gunnarsson, I. et al. Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide-resistant proliferative lupus nephritis. Arthritis Rheum. 56, 1263–1272 (2007).

    CAS  PubMed  Google Scholar 

  133. Lim, C. C. et al. Severe infections in patients with lupus nephritis treated with immunosuppressants: a retrospective cohort study. Nephrology 22, 478–484 (2017).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of A.R.P.S. is supported by the European Union’s Horizon 2020 research and innovation programme support for the Amsterdam Rheumatology Center for Autoimmune Diseases (ARCAID; grant number 847551).

Author information

Authors and Affiliations

  1. Amsterdam Rheumatology Center ARC, Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centre, Amsterdam (North Holland), the Netherlands

    Agner R. Parra Sánchez, Alexandre E. Voskuyl & Ronald F. van Vollenhoven

Authors
  1. Agner R. Parra Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandre E. Voskuyl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald F. van Vollenhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.R.P.S. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and/or edited the manuscript before submission.

Corresponding author

Correspondence to Ronald F. van Vollenhoven.

Ethics declarations

Competing interests

R.F.v.V. declares that he has received research support (institutional grants) from BMS, GSK, Lilly and UCB and support for educational programmes from Pfizer and Roche. R.F.v.V. declares that he has also received consulting fees from AbbVie, AstraZeneca, Biogen, Biotest, BMS, Galapagos, Gilead, Janssen, Pfizer, Sanofi, Servier, UCB and Vielabio and personal honoraria as a speaker from AbbVie, Galapagos, GSK, Janssen, Pfizer and UCB. A.E.V. declares that he has received research support (institutional grants) from GSK and UCB, consulting fees from GSK, AstraZeneca and Roche, and personal honoraria as a speaker from GSK. A.R.P.S. declares no competing interests.

Additional information

Peer review information

Nature Reviews Rheumatology thanks C.C. Mok and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parra Sánchez, A.R., Voskuyl, A.E. & van Vollenhoven, R.F. Treat-to-target in systemic lupus erythematosus: advancing towards its implementation. Nat Rev Rheumatol 18, 146–157 (2022). https://doi.org/10.1038/s41584-021-00739-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-021-00739-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing