Our understanding of the pathophysiological mechanisms in systemic lupus erythematosus (SLE) has increased over the years and with that came the hope that more effective therapies could be developed; however, progress in the therapeutic area has been slow. An appreciation of the important role of autoantibody producing B-lymphocyte-derived plasma cells in SLE led to the development and subsequent approval of a B-cell specific biological therapy, belimumab.^1–3 As could have been expected, this treatment was shown to be most effective in patients with anti-DNA antibodies and complement activation.⁴ Perhaps surprisingly, the efficacy of this treatment in lupus nephritis, the manifestation of SLE most closely associated with the highly specific anti-DNA antibodies, remained incompletely established until a recent large randomised clinical trial demonstrated convincing efficacy when belimumab was added to standard background treatment in patients with progressive lupus nephritis.⁵

Moreover, improved understanding of the cellular processes involved in nephritis and the development of proteinuria supported the development of voclosporin, which demonstrated efficacy in a Phase 3 clinical trial.⁶

Meanwhile, other pathophysiological pathways in SLE also attracted attention. Both interleukin (IL)-12 and IL-23 were shown to be involved in aspects of SLE, and a Phase 2 clinical trial demonstrated efficacy for the IL-12/23 inhibitor ustekinumab. Blocking multiple cytokines using the JAK inhibitor baricitinib was also effective in a Phase 2 trial.⁷

The role of the type 1 interferon (IFN) pathway in SLE has been under intense scrutiny for many years. Pioneering work by Rönnblom and other investigators demonstrated the presence of interferon and interferon-related gene activation in the majority of patients with SLE,⁸ and identified the plasmacytoid dendritic cell (pDCs) as the source of excessive IFN in this disease. An etiological link between defective clearance of nuclear breakdown products and excess IFN may be the most central immunological deviation in this complex disease. Following a successful Phase 2 trial, two Phase 3 trials of the IFN-receptor antagonist anifrolumab demonstrated efficacy in a range of outcomes.⁹ Early studies with a monoclonal directed against the pDC marker BDCA2 also showed clinical efficacy.¹⁰

Based on these developments taken together, it is now correct to say that for understanding and treating SLE, a new era is dawning.

Learning Objectives

• Demonstrate understanding of the key pathophysiological mechanisms in SLE

• Describe the different therapeutic targets in SLE and the importance of new drug development aimed at these

• Discuss how the therapeutic landscape in SLE may evolve in the near future

References

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(12):3918–30.

2. Navarra SV, Guzman 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(9767):721–31.

3. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009;61(9):1168–78.

4. van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 2012;71(8):1343–9.

5. Furie R, Rovin BH, Houssiau F, et al. OP0164 BLISS-LN: A randomised, double blind, placebo-controlled phase 3 trail of intravenous belimumab in patients with active lupus nephritis. Ann Rheum Dis 2020;79(Suppl 1):103–03.

6. Arriens C, Polyakova S, Adzerikho I, et al. OP0277 AURORA PHASE 3 STUDY DEMONSTRATES VOCLOSPORIN STATISTICAL SUPERIORITY OVER STANDARD OF CARE IN LUPUS NEPHRITIS (LN). Ann Rheum Dis 2020;79(Suppl 1):172–73.

7. Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2018;392(10143):222–31. doi: 10.1016/s0140-6736(18)31363-1.

8. Ronnblom L, Leonard D. Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med 2019;6(1):e000270. doi: 10.1136/lupus-2018-000270 [published Online First: 2019/09/10]

9. Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med 2019;382(3):211–21.

10. Furie R, Werth VP, Merola JF, et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J Clin Inv 2019;129(3):1359–71.