PRSYM—At the 2021 Pediatric Rheumatology Symposium (PRSYM), a session on lupus provided a robust discussion of recent advances in lupus treatments and genetic discoveries in pediatric rheumatology.
Dr. Jackson
Lupus Nephritis
The first speaker was Shaun Jackson, MD, PhD, a pediatric nephrologist and rheumatologist and associate professor at Seattle Children’s. His presentation focused on state-of-the-art treatments in proliferative lupus nephritis, highlighting several recent advances in lupus nephritis research and treatment.
In clinical trials, patients who received voclosporin, in combination with standard therapy (i.e., mycophenolate mofetil and low-dose steroids), experienced statistically significant improvement in renal outcome measures. These findings included a significant reduction in urine protein levels, which is the most important predictor of long-term outcomes.
Moreover, the investigators saw early differences in the amount of proteinuria, Dr. Jackson explained. He displayed two Kaplan-Meier plots showing time to complete remission and time partial remission, measured by improvements in the urine to protein creatinine ratio (UPCR). To meet complete remission, patients needed a UPCR of less than 0.5 mg/mg, and partial remission was defined as a 50% reduction in proteinuria. The Kaplan-Meier plots showed separation between patients receiving voclosporin and those receiving placebo as early as four weeks. The study continued to demonstrate improvement in proteinuria, and voclosporin ultimately met the primary endpoint of complete renal response at 52 weeks, in addition to several secondary endpoints.2
As promising as these results are, Dr. Jackson said they should be interpreted with caution. Like other calcineurin inhibitors, voclosporin reduces protein in the urine in one of two ways. First, as a targeted T cell therapy, it acts as an immunosuppressant, blocking T cell signaling and activation. Second, it has direct effects on podocytes, specific cells in the kidney, directly decreasing the amount of protein in the urine. Some early benefits of voclosporin may be related to the second mechanism of action rather than its effects on the immune system.
Other options: Targeted B cell therapy has also recently shown some promise. Dr. Jackson highlighted recent research on belimumab and newer anti-CD20 agents. Belimumab is a monoclonal antibody that targets B cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS). In clinical trials, belimumab showed modest—but statistically significant—improvement in renal outcomes when added to baseline immunosuppression.3 In December 2020, it became the first drug approved by the FDA to treat adults with lupus nephritis. Intravenous belimumab is also FDA approved to treat children older than 5 with systemic lupus erythematosus who are receiving standard care.
Another potential method of targeting B cells is through B cell depletion with anti-CD20 agents, such as rituximab. In a previous large clinical trial, rituximab failed to show a benefit in lupus nephritis.4 However, Dr. Jackson suggested this may be due to incomplete B cell depletion with rituximab. Newer anti-CD20 agents, such as obinutuzumab, have enhanced B cell depletion and may prove viable therapeutic options for lupus nephritis. A phase 2 trial is ongoing, but Dr. Jackson reported interim analysis of unpublished data that at the one-year mark do show some benefit.
For pediatric lupus nephritis, clinicians still lack FDA-approved treatment options, but the growing options for adult patients provide hope that pediatric options won’t be far behind. As technology, such as single-cell RNA sequencing, advances, Dr. Jackson believes this will help elucidate the pathophysiology of lupus nephritis and provide more targets for future therapies. Questions remain with such agents as voclosporin, belimumab and obinutuzumab, especially in pediatric rheumatology. But this research provides hope for future clinical trials and treatment advances.
Dr. Vogel
Monogenic Lupus
The session’s second speaker was Tiphanie Vogel, MD, PhD, an assistant professor and pediatric rheumatologist at Baylor College of Medicine and Texas Children’s Hospital, Houston. She discussed updates in monogenic lupus.
Dr. Vogel began her presentation discussing three children with a new diagnosis of lupus, highlighting the heterogeneity of the disease. According to Dr. Vogel, genetic and deep-immune profiling tools should allow us to work toward a time when we can meaningfully subgroup our patients in ways that are diagnostically and therapeutically helpful to their care. Although cases of monogenic lupus are rare and contribute only a fraction of the overall heritability, they can significantly inform the pathogenesis and mechanisms of lupus.
Several mechanisms of monogenic lupus have been described and can be grouped into different pathways. Dr. Vogel said these genetic mutations can be related to complement dysregulation, poor apoptotic clearance, poor lymphocyte tolerance and poor nucleic acid sensing leading to enhanced interferon signaling. It’s important to remember these pathways are very interconnected, and it can be helpful to think about how certain disorders may fit into the different groups. This approach is critical to understanding lupus and to the development of better diagnostics and therapeutics.
Dr. Vogel also discussed several causes of monogenic lupus, including those that result in classic lupus, those that mimic lupus but can cause a more predominant feature, and those that cause additional significant non-lupus-like features. She said clinicians should consider genetic sequencing for patients presenting with extreme phenotypes, including patients with early-onset disease, atypical features, disease that is refractory to treatment or progressive despite treatment, and patients with an atypical family history.
As genetic sequencing becomes more widely used, Dr. Vogel expects we will continue to discover new genes involved in the pathogenesis of lupus and improve our understanding of their genetic burden.
Dr. Hedrich
Extra-Renal Lupus
The final speaker was Christian Hedrich, MD, PhD, a pediatric rheumatologist and professor, Women’s & Children’s Health, Liverpool, U.K. His presentation focused on the management of extra-renal juvenile systemic lupus erythematosus (jSLE).
He reiterated that lupus is a highly complex disease with a variable phenotype that can affect essentially any part of the body. Unlike those with monogenic disease, most children who develop lupus have some genetic predisposition, but require other triggers, such as environmental factors, hormonal influences or other events. He said jSLE accounts for 10–20% of all SLE cases. The average age of onset is 12 years. In contrast to adults with SLE, children with SLE experience higher disease activity at diagnosis, with more organ involvement and complications. Also, children with SLE often require more immunosuppression, which according to Dr. Hedrich, suggests that treatments are not as effective in jSLE as they are in adult SLE.
Dr. Hedrich continued with an overview of the SHARE (Single Hub and Access Point for Paediatric Rheumatology in Europe) guidelines for the diagnosis and treatment of jSLE.5 These guidelines include recommendations for all patients with jSLE to receive hydroxychloroquine to control disease activity and reduce disease flares. Other recommendations include the addition of disease-modifying anti-rheumatic drugs (DMARDs) when corticosteroids are insufficient to control non-renal disease and the use of rituximab if DMARDs are inadequate. Guidelines such as these can be helpful because rituximab is not recognized or licensed for treatment of jSLE in all countries.
Dr. Hedrich then presented data from the U.K. jSLE cohort, including evidence of a wide variation in treatment strategies. Following the release of the SHARE recommendations, data show an increased use of additional treatments, including rituximab, in patients with an inadequate response to corticosteroids.
Researchers have also used the U.K. cohort to investigate how ethnicity and age-related phenotypes in jSLE may inform treatment decisions. In the cohort, they found Black patients presented with symptoms at a younger age and with greater female predominance. Correlations were also found between disease manifestations and treatments.6 When stratifying for age, researchers also observed differences in disease manifestations between children who presented with jSLE prior to puberty, during puberty and in adolescence.7
With this information, Dr. Hedrich said subgroups of patients may exist within pediatric age groups, including those with monogenic lupus who present early in life, those with a higher genetic predisposition due to a number of risk alleles and a third group who may have some risk alleles but must accrue additional risk factors over time.
As researchers continue to identify genes that contribute to the development of lupus, Dr. Hedrich hopes clinicians will be able to stratify patients according to their molecular makeup, which may enable the prediction of treatment responses and, ultimately, pave the way for personalized medicine in pediatric lupus.
In Sum
Although options for the treatment of children with lupus have been limited historically, genetic studies have provided several advances in therapeutics and to our understanding of the pathophysiology of lupus. In the future, new genetic causes of lupus may be identified and may lead to new therapeutic targets and personalized treatment plans.
Elizabeth Sloan, MD, is a pediatric rheumatologist who recently completed her fellowship training at UT Southwestern Medical Center, Dallas, and looks forward to joining the faculty of the Division of Pediatric Rheumatology at UT Southwestern in the fall of 2021. Dr. Sloan has also served on the ACR FIT Subcommittee and the ACR Special Committee on Pediatric Rheumatology.
References
- Arazi A, Rao DA, Berthier CC, et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol. 2019 Jul;20(7):902–914.
- Rovin BH, Solomons N, Pendergraft WF 3rd, 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. 2019 Jan;95(1):219–231.
- Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020 Sep;383(12):1117–1128.
- 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.
- Groot N, de Graeff N, Avcin T, et al. European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupus erythematosus: The SHARE initiative. Ann Rheum Dis. 2017 Nov;76(11):1788–1796.
- Massias JS, Smith EM, Al-Abadi E, et al. Clinical and laboratory phenotypes in juvenile-onset systemic lupus erythematosus across ethnicities in the UK. Lupus. 2021 Apr;30(4):597–607.
- Charras A, Smith E, Hedrich CM. Systemic lupus erythematosus in children and young people. Curr Rheumatol Rep. 2021 Feb;23(3):20.
