Toward Personalized Medicine in Pediatric Lupus

WASHINGTON, D.C.—Kids with lupus get really sick. Widespread corticosteroid use remains the norm, and side effects can be particularly nasty in growing and developing children. The diagnosis is difficult to make, disease activity monitoring isn’t straightforward, and currently no helpful predictors of end-organ involvement exist. Therapeutic options remain a concern too, with only one of three U.S. Food & Drug Administration-approved drugs approved for systemic lupus erythematosus (SLE) in the past 65 years validated for childhood-onset SLE (cSLE).

Dr. Virginia Pascual

The good news? Researchers are using novel technologies to push the needle closer toward personalized medicine in cSLE every day. At the ACR Convergence 2024 session Toward Personalized Medicine in Pediatric Lupus, Virginia Pascual, MD, director, Drukier Institute for Children’s Health and Ronay Menschel Professor of Pediatrics, Weill Cornell Medical College, New York, shared insights into where we are and where we are going when it comes to better understanding cSLE.

Novel Techniques Explained

Sequencing techniques and new approaches are helping researchers better understand the complex causes of cSLE by looking at the disease from many angles. Methods like whole genome sequencing (WGS) and RNA sequencing allow scientists to study genetic changes and differences in gene activity that may play a role in the development of disease. By identifying specific genes and immune pathways that are disrupted in the disease, we may find new ways to diagnose and treat cSLE earlier.

Additionally, “-omics” methodologies allow researchers to study large groups of molecules at once. These include genomics (studying genes), transcriptomics (studying gene activity), proteomics (studying proteins) and metabolomics (studying small molecules that are involved in metabolism). By looking at all these molecules at once as one big picture, researchers can better understand how they work together to affect health and disease, providing insights that are difficult to get from studying just one molecule at a time.

SLE Is an Interferonopathy

We have understood that increased interferon (IFN) activity is a hallmark of SLE for over 20 years.¹ However, Dr. Pascual explained, “We have learned over the years that it’s not that simple. And the most clear hint to that is that, today, we can target the type I IFN pathway in different ways, including blocking the type I IFN receptor [with anifrolumab]. This [method] works well for many patients, especially those with cutaneous SLE, but it’s not for every patient with systemic or renal disease. We’ve made great advances, but we aren’t yet there.”^2,3

Different Types of SLE

As with adult SLE, both the clinical manifestations and pathogenesis of cSLE are heterogeneous. WGS reveals a monogenic (familial) underlying cause in less than 15% of patients with cSLE, and about 130 common allelic variants are associated with the risk of developing SLE.⁴ Interestingly, studying monogenic lupus has enabled the discovery of different pathways that induce the SLE phenotype.^4,5

SLE can arise from deficiencies, among others, in the complement/immune complex removal system or intra- and extra-cellular nucleic acid degradation system. Loss of B cell tolerance due to intrinsic B cell defects is also a major contributor. Dr. Pascual explained, “The majority of the genetic mutations identified so far that predispose to early onset SLE result in an increase in IFN pathway activity. Overall, however, different pathways upstream of interferon can induce the SLE phenotype.”⁶

By monitoring the immune systems of patients to identify cell types and gene expression patterns that correlate with disease flares and remissions, different groups of patients with cSLE have been identified.⁷ Future studies aim to elucidate differences between these groups, especially as it pertains to using this information to design clinical trials and apply personalized therapies to eventually test the value of cellular and transcriptional biomarkers.

Why Are These Data Important?

“Data like [these are] important because industry is developing drugs to block a wide variety of targets within the pathways that have been identified through genomics and immune monitoring technologies,” Dr. Pascual said. “Work like this is opening the possibility for much more personalized therapies or combinations of therapies. And we need to figure out in which patients these may work in order to avoid cumulative or irreversible damage.”

In Sum

Novel techniques offer hope for developing personalized therapies that are tailored to a person’s specific genetic and biological makeup, hopefully leading to better outcomes. “We are trying to classify our patients into the right molecular group. The better we characterize their underlying immune dysregulation, the more accurately and hopefully successfully we can treat them,” Dr. Pascual concluded.

Samantha C. Shapiro, MD, is a clinician educator who is passionate about the care and education of rheumatology patients. She writes for both medical and lay audiences and practices telerheumatology.

References

1. Bennett L, Palucka AK, Arce E, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003 Mar 17;197(6):711–723.
2. Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221.
3. Jayne D, Rovin B, Mysler E, et al. Anifrolumab in lupus nephritis: Results from second-year extension of a randomised phase II trial. Lupus Sci Med. 2023 Aug;10(2):e000910.
4. Omarjee O, Picard C, Frachette C, et al. Monogenic lupus: Dissecting heterogeneity. Autoimmun Rev. 2019 Oct;18(10):102361.
5. Qin Y, Ma J, Vinuesa CG. Monogenic lupus: Insights into disease pathogenesis and therapeutic opportunities. Curr Opin Rheumatol. 2024;36(3):191–200.
6. Vinuesa CG, Shen N, Ware T. Genetics of SLE: Mechanistic insights from monogenic disease and disease-associated variants. Nat Rev Nephrol. 2023 Sep;19(9):558–572.
7. Banchereau R, Hong S, Cantarel B, et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell. 2016 Apr 21;165(3):551–565.