ACR BEYOND LIVE—Among patients with systemic lupus erythematosus (SLE), lupus nephritis remains one of the leading causes of mortality, and patients with both SLE and end-stage renal disease demonstrate standardized mortality ratios higher than 60 times that of patients with SLE who have normal kidney function.1 Although the ACR Guidelines for Screening, Treatment, and Management of Lupus Nephritis, published in 2012, appear to be straightforward in terms of choices for induction and maintenance therapies, the complex biology and heterogeneous phenotypes of lupus nephritis make the story more complicated.2
At the 2020 ACR State-of-the-Art Clinical Symposium, Joan Merrill, MD, director of clinical projects in the Arthritis & Clinical Immunology Research Program at the Oklahoma Medical Research Foundation, Oklahoma City, discussed updates in the understanding and treatment of lupus nephritis.
Dr. Merrill began her talk by noting several baseline characteristics of patients with lupus nephritis that may portend a poor prognosis, such as non-European ancestry, young age, elevated serum creatinine or chronicity index, class IV lesions on biopsy, and anti-Ro antibodies. In particular, she stated that it’s important to pay attention to tubulointerstitial involvement on renal biopsy, because it may be a significant indicator of high risk for progression to renal failure.3
Many rheumatologists are aware of such options as cyclophosphamide or mycophenolate mofetil as induction treatment for lupus nephritis, but the most exciting areas of research in lupus nephritis include the evolving comprehension of how factors specific to each patient and their expression of disease may guide treatment. For example, the 2012 ACR guidelines point out that mycophenolate mofetil is preferred over cyclophosphamide as induction therapy for class III and IV lupus nephritis in African American and Hispanic patients.2
A randomized trial of multi-target induction therapy with tacrolimus plus mycophenolate mofetil vs. cyclophosphamide alone in patients with lupus nephritis across 26 renal centers in China showed multi-target treatment was superior in this population, and this has had important implications for use of calcineurin inhibitors in Asian patients with lupus nephritis.4
Partnership for Drug Targets
On a molecular level, researchers since 2003 have been investigating the prominent expression of interferon (IFN) regulated genes—an IFN signature—in the blood and tissues of patients with SLE, prompting such questions as: What is the cause of the IFN signature? Which cells produce IFN and does this change over different phases of the disease? Should treatment focus on blocking the IFN system in SLE and, if so, which is the most suitable target?5
Understanding the role the IFN signature plays in predicting prognosis and choosing therapy for patients with lupus will undoubtedly be part of the future of rheumatology. Already, the National Institutes of Health (NIH), pharmaceutical companies and nonprofit organizations have come together to create the Accelerating Medicines Partnership (AMP), which is looking at disease-specific pathways, such as IFN expression in SLE, to identify relevant drug targets for treatment.
Combination Therapy
An essential part of optimizing treatment of lupus nephritis is knowing when and how to employ combination therapy (i.e., using more than one immunosuppressant at a time to prevent worsening renal involvement), Dr. Merrill explained.
She was clear that not all combination therapies are superior to monotherapy; for example, adding one medication to another can sometimes result in redundant or even deleterious effects. The key is to know which treatments may act synergistically to improve overall efficacy. Much of the lecture was spent discussing studies that have looked at different combination therapies for lupus nephritis.
In 2018, researchers in China reported a 24-week trial of 191 patients with lupus nephritis who were randomized to receive either intravenous cyclophosphamide alone or a combined immunosuppressive treatment regimen with intravenous cyclophosphamide, an oral immunosuppressive agent (mycophenolate mofetil, azathioprine or leflunomide) and hydroxychloroquine.6 The primary endpoint was complete remission as defined by proteinuria <150 mg per 24 hours and normal urinary sediment, serum albumin and renal function at 24 weeks.
At week 24, both the rate of complete remission and total response were higher in the combined group than in the cyclophosphamide monotherapy group, and no difference between the two arms was found in the incidence of severe adverse events.
This study indicates it may be possible to safely and effectively combine medications with cyclophosphamide to increase the likelihood of complete remission in patients with lupus nephritis, although more work will be needed to replicate these results, to see if they are generalizable outside of China, and to identify if factors exist that can predict which oral immunosuppressive agents to choose for individual patients.
Rituximab, which is included in the ACR guidelines, has been studied in a randomized, double-blind, placebo-controlled, phase 3 trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil and corticosteroids.7 A total of 144 patients with class III or class IV lupus nephritis were randomized to receive rituximab or placebo at 0 and 6 months and the primary endpoint of renal response status was assessed at week 52. Although rituximab did not demonstrate statistically significant improvement in clinical outcomes after one year of treatment, the combined complete and partial response proportion was 11% higher in the rituximab group as compared to the placebo group.
Dr. Merrill discussed several other medications that, although they did not reach statistical significance, demonstrated trends toward efficacy when used as part of combination therapy. These included obinutuzumab, a type II, anti-CD20 monoclonal antibody, which, in the randomized, double-blind, placebo-controlled NOBILITY trial, was combined with mycophenolate mofetil in treating 125 patients with proliferative lupus nephritis and showed increased complete and partial renal responses compared to placebo.8
There was also discussion of an ongoing phase 3 trial of voclosporin, a novel calcineurin inhibitor.9 In this study of more than 350 patients with active lupus nephritis, publicly available data of the results so far have shown that combining voclosporin with mycophenolate mofetil and low-dose corticosteroids was superior to standard care for treating patients with lupus nephritis. Further information will need to be released to confirm the results, but the prospects of this medication seem potentially promising.
Future Strategies
For a condition in desperate need of additional treatment strategies to prevent progression and ultimately renal failure, the advances and thought-provoking ideas discussed by Dr. Merrill offer hopeful glimpses of the future for patients with lupus nephritis. In partnership with patients and with a clear understanding of the evolving literature, clinicians can help patients live longer, healthier lives.
Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.
References
- Mok CC, Kwok RC, Yip PS. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheum. 2013 Aug;65(8):2154–2160.
- Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012 Jun;64(6):797–808.
- Hsieh C, Chang A, Brandt D, et al. Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken). 2011 Jun;63(6):865–874.
- Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: A randomized trial. Ann Intern Med. 2015 Jan 6;162(1):18–26.
- Rönnblom L, Leonard D. Interferon pathway in SLE: One key to unlocking the mystery of the disease. Lupus Sci Med. 2019 Aug 13;6(1):e000270.
- An Y, Zhou Y, Bi L, et al. Combined immunosuppressive treatment (CIST) in lupus nephritis: A multicenter, randomized controlled study. Clin Rheumatol. 2019 Apr;38(4):1047–1054.
- Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012 Apr;64(4):1215–1226.
- Furie R, Aroca G, Alvarez A, et al. A phase II randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of obinutuzumab or placebo in combination with mycophenolate mofetil in patients with active class III or IV lupus nephritis [abstract 939]. Arthritis Rheumatol. 2019;71(suppl 10).
- Gibson K, Parikh S, Saxena A, et al. AURORA phase 3 trial demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (LN) [abstract 407]. National Kidney Foundation 2020 Spring Clinical Meetings. 2020.