The recent approvals of treatments that, when added to established background therapies, significantly increase response rates in systemic lupus erythematosus (SLE) is exciting. These approvals include belimumab and voclosporin for lupus nephritis (LN), and the anticipated approval of anifrolumab for cutaneous and musculoskeletal SLE, with several more treatments in the pipeline. And yet, 40–50% of patients in trials do not reach the desired improvement. Achieving lupus low disease activity score (LLDAS) maintained for one year occurs in only 50% of patients. The proportion of LN patients reaching end stage kidney disease (ESKD) has not declined in the last decade. Furthermore, the problems of serious adverse events identified in every clinical trial pose hazard to quality and quantity of life.

The unmet needs evident in these trials are:

1. Earlier diagnosis and treatment

2. Strategies to identify responders early

3. Strategies to anticipate flares before they are clinically apparent

4. Optimization of background therapies

5. Even better new treatments or combination therapies

6. Reduction of risk for damage and death

In LN, delaying renal biopsy by 3 months increases risk of poor outcomes and delaying by 6 months increases risk of end-stage kidney disease by 9-fold.^{1, 2} In a California study of LN patients with government insurance (Medicaid), only 31% were treated with immunosuppressive approaches 1 year after diagnosis.³ Added to these disturbing delays are problems with patients’ treatment compliance, which is well less than 60% in many populations. It is also important to identify responders early, with LN there is a strong association between good outcome and decline in proteinuria, with the goal of ≤0.7/24 hours at one year associated with better outcomes.⁴ Several laboratories are reporting panels of cytokines/chemokines and other proteins in serum or urine that predict lupus flare; none are yet widely available for clinical use. Regarding background therapies, all SLE patients that can tolerate it should receive hydroxychloroquine, since it reduces mortality by 35% (over 12 years). Reducing prednisone to the lowest dose possible is also a major goal, whilst finding the balance between damage from active disease and that caused by prednisone and other treatments. Some of the interesting new treatments in clinical trials include inhibition of plasmacytoid dendritic cell activation (a major source of interferon type 1), antibodies to CD20 that are more depleting and less immunogenic than rituximab, and inhibitors of pathways activated by cytokines and receptors in and on B and T cells. Finally, close attention to preventing damage (in addition to reducing immunosuppression) will improve quality and quantity of life, including prevention of infections (COVID vaccination is recommended for SLE patients), accelerated atherosclerosis and osteoporosis with fractures.

In conclusion, the recent advances are transformative in that we can suppress disease activity to protect from organ damage in increasingly higher proportions of patients with SLE, but there is a long way to go and much hard thinking lies ahead.

Learning Objectives

• Describe the efficacy of novel treatment interventions and combinations in improving outcomes in patients with SLE/LN

• Discuss current unmet needs in the management of SLE/LN and how novel treatments may overcome these

• Explain the need for the improving fast access to treatment, whilst minimizing costs and adverse treatment effects, and the importance of educating patients and caregivers about these

References

1. Faurschou M, Starklint H, Halberg P, Jacobsen S. Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol. 2006;33(8):1563–9.

2. Ioannidis JP, Boki KA, Katsorida ME, et al. Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney Int. 2000;57(1):258–64.

3. Yazdany J, Feldman CH, Liu J, et al. Quality of care for incident lupus nephritis among Medicaid beneficiaries in the United States. Arthritis Care Res (Hoboken). 2014;66(4):617–24.

4. Tamirou F, Lauwerys BR, Dall’Era M, 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. 2015;2(1):e000123.