Recent research by Joo and colleagues at The Catholic University of Korea, Department of Rheumatology has shown that for many lupus nephritis patients, the cure may be at least as damaging as the disease in terms of organ damage.^[1]

Lupus nephritis, which occurs when lupus auto-antibodies affect the kidneys, is one of the most serious manifestations of systemic lupus erythematosus (SLE). It is a predictor of organ damage and a strong determinant of survival in SLE, which affects around 200,000 US adults.^[1]

Among patients with lupus, 40-50% develop lupus nephritis within five years of diagnosis and at least 10% of those ultimately develop end stage renal disease (ESRD), requiring dialysis or kidney transplantation.^[2,3]

Renal failure remains one of the major causes of death in lupus nephritis, a condition characterized by high levels of inflammation requiring immunosuppressive agents such cyclophosphamide and high-dose glucocorticoids. Both the inflammation and treatments contribute to organ damage in lupus nephritis, and until recently it wasn’t known which had the biggest impact.^[1]

The question was recently answered by Joo and colleagues, who set out to differentiate the different types of organ damage seen in lupus nephritis and compare standardized mortality rates in lupus patients with (n = 515) and without lupus nephritis (n = 597). The study included patients enrolled in the Hanyang BAE Lupus observational cohort between 1998 and 2012.^[1]

Lupus nephritis associated with increased steroid exposure and higher levels of organ damage

Clinical data are collected annually on this cohort, including organ damage assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) SLE Damage Index (SDI). Joo and team compared data on renal and non-renal organ damage; the latter was determined by excluding renal damage endpoints from the damage index. Non-renal associated damage was further classified based on known steroid-association, e.g., diabetes and osteoporosis.

Significant (p = <0.003) differences were found between the patients with and without lupus nephritis:

• Higher proportion of male patients (9.1% / 5.0%)
• Longer disease duration (10.0 years / 8.7 years)
• Higher percentage use of glucocorticoids (98.8% / 93.6%)
  • Higher cumulative exposure to glucocorticoid steroids (27.0g / 14.2g)
• Higher level of organ damage (cumulative SDI 1.2 / 0.6)
  • SDI > 1 (51.5% / 35.7%)
  • Renal SDI > 1 (21.9% / 0.0%)

Lupus nephritis associated with high mortality rates and steroid-related organ damage

Overall, 17.7% of patients developed steroid-associated damage, with the most prevalent manifestations being avascular necrosis and cataracts. Patients with lupus nephritis (22.7%) were much more likely to experience steroid-related damage than those without (9.8%). Patients with lupus nephritis (14.8%) were less likely to experience non-steroid related damage than those without lupus nephritis (21.3%).  

These results are consistent with findings in systemic lupus erythematosus overall, as outlined by lupus expert Michelle Petri, who notes that up to 80% of organ damage in systemic lupus erythematosus is caused by steroids.  

The study included follow-up from 114 patients and reported 53 deaths. Comparison of standardized mortality rates between all patients and patients with/without lupus nephritis found mortality rates with lupus nephritis (5.17, 95% CI 3.49-7.38) were more than double than in patients without lupus nephritis (2.32, 95% CI 1.47-3.48).

Why is this important?

The key finding is that most of the organ damage seen in patients with lupus nephritis is caused by the steroids used to treat the disease. This underlines the need for new steroid-sparing therapies to minimize organ damage.   

The good news is that progress is being made in this direction, with two new therapies recently approved for lupus nephritis: belimumab, a monoclonal antibody against B-lymphocyte stimulator (BLyS) and voclosporin, a calcineurin inhibitor. Both drugs have proven efficacy in reducing renal damage^.[3]

In parallel, there has been a focus on the development of new tools to measure steroid-toxicity to support the development of steroid-sparing therapies. A recent study using the Steritas Glucocorticoid Toxicity Index (GTI) in lupus nephritis patients demonstrated that GTI scores correlated with cumulative glucocorticoid exposure at 5 years.^[4] 

The GTI is part of the STOX® Suite, which includes the pGTI and GTI-MD, and has been used in over 80 clinical trials across 28 disease areas and 1100 clinical sites including pediatric systemic lupus erythematosus. The uptake of the STOX suite underlines the growing awareness of the importance of quantifying steroid-toxicity in clinical development for inflammatory diseases.
 

References

1. Joo YB, Won S, Choi C-B and Bae S-C.  Lupus nephritis is associated with more corticosteroid-associated organ damage but less corticosteroid non-associated organ damage.  Lupus 26:598-605, 2017. DOI: 10.1177/0961203316671813
2. Bechler KK, Stolyar L, Steinberg E et. al. Predicting patients who are likely to develop lupus nephritis of those newly diagnosed with systemic lupus erythematosus.  AMIA Annu. Symp. Proc. 2022: 221-230, 2023. PMID: 37128416 PMCID: PMC10148321
3. Gasparotto M, Gatto M, Binda V, Doria A and Moroni G.  Lupus nephritis:  clinical presentations and outcomes in the 21st century.  Rheumatology 59: v39-v51, 2020. doi:10.1093/rheumatology/keaa381
4. Usiskin IM and Kyttaris VC.  Estimating glucocorticoid-related morbidity in lupus nephritis using the glucocorticoid toxicity index.  Lupus 32(4):565-570, 2023. DOI: 10.1177/09612033231160969