ACR CONVERGENCE 2021—Patients with systemic lupus erythematosus (SLE) don’t have many approved drugs for treatment. In fact, only three lupus-specific drugs have been produced in the past few decades, with two of them approved in the past year.
Dr. Virginia Pascual
“You’ll agree we are not doing well when we compare [treatment options for lupus] to rheumatoid arthritis or many of the other diseases we encounter in the clinic,” said Virginia Pascual, MD, director of the Drukier Institute for Children’s Health and the Ronay Menschel professor of pediatrics at Weill Cornell Medicine Gale and Ira Drukier Institute for Children’s Health, New York City.
Still, researchers continue to explore additional options for lupus patients, including the possibility of precision medicine. Dr. Pascual addressed potential precision targets during the Precision Medicine in Lupus session at this year’s ACR Convergence.
The State of Lupus Treatments
Rheumatologists continue to rely on the small number of therapies available for lupus, as well as glucocorticoids for first-line treatment, even knowing the tremendous side effects the latter therapy can cause, Dr. Pascual said. Many clinical trials related to lupus have failed, including various approaches targeting B cells, co-stimulatory molecules and the interferon pathway, all of which are known contributors to the pathogenesis of disease.
One challenge of precision medicine within lupus is the heterogeneity of the disease. When asked if a single therapy can be developed for such a highly heterogenous disease, Dr. Pascual said she didn’t think so. “Maybe in the future we’ll come to a generalized metabolic alteration that will be targeted by one approach, but this remains to be seen,” she said. “These are different ways to get a lupus phenotype, and we should better understand where each of our patients came from. Either we stratify properly, or it will be difficult to treat everyone the same way.”
Genetics is providing clues for clinicians to better comprehend the complexity of lupus, Dr. Pascual said. “Genetic studies are teaching us that not all mutations leading to lupus result in the same sub-phenotype,” she said. Still, most patients don’t have familial lupus, and every effort should be made to characterize their immune profiles to enable personalized treatments.
2 Studies Shed Light
Dr. Pascual presented the results from several studies that drilled down on the heterogeneity of lupus to better identify treatment targets. One study she shared, from Nehar-Belaid et al., was published in 2020 and focused on profiling approximately 276,000 peripheral blood mononuclear cells (PBMCs) from 33 children with SLE and 11 matched controls.1 Those with SLE had an increased expression of interferon-stimulated genes derived from a group of transcriptionally defined subpopulations that are part of major cell types. These included monocytes, conventional dendritic cells, plasmacytoid dendritic cells, B cells and others. Study researchers then profiled roughly 82,000 PBMCs from adult patients with SLE and found the expansion of these same subpopulations in those with the highest disease activity.
These types of studies can bring us closer to SLE transcriptional signatures and precision medicine possibilities, the study researchers concluded. This is an example of how the results from studies done in children with SLE should be applicable to adults as well, Dr. Pascual explained.
Another study Dr. Pascual reviewed, by Caielli et al. and published this year, focused on mitochondrial dysfunction within SLE pathogenesis.2 Specifically, researchers showed that programmed mitochondrial removal in the red blood cell lineage is defective in a group of SLE patients.
Caielli et al. demonstrated that when human erythroid cell maturation takes place, a hypoxia-inducible factor-mediated metabolic switch leads to the activation of the ubiquitin-proteasome system. This is needed to induce mitophagy and final mitochondrial removal, but a defect in this pathway can lead to mature red blood cells that carry mitochondria. When internalized by macrophages, these red blood cells induce a strong interferon response. SLE patients displaying red blood cells carrying mitochondria as well as anti-red blood cell antibodies, which facilitate their opsonization by macrophages, have the highest levels of blood interferon-stimulated gene signatures. This is yet another example of a unique collaboration between lupus autoantibodies and unusual endogenous nucleic acids contributing to lupus pathogenesis, the researchers concluded.
Future Possibilities
These studies provide insights into potential markers toward precision medicine avenues for lupus, and research continues to find promising lupus targets and biomarkers that might enable precision medicine in the near future. “In the meantime, while some of the therapies currently in development will hopefully show success in phase 3 clinical trials, failures might result from the enrollment of highly heterogeneous patients within the same trial,” Dr. Pascual said.
A rational trial design based on patient molecular and overall immune stratification will lead the way toward precision medicine for lupus, Dr. Pascual said. Contributions from granulocytes, erythroid lineage cells, dysregulated metabolic pathways and novel autoantibodies will remain part of the quest.
“What we’ve witnessed in the past five years is an explosion of information in the right direction,” Dr. Pascual said.
Vanessa Caceres is a medical writer in Bradenton, Fla.
References
- Nehar-Belaid D, Hong S, Marches R, et al. Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat Immunol. 2020 Sep;21:1094–1106.
- Caielli S, Cardenas J, Almeida de Jesus, et al. Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Cell. 2021 Aug 19;184:4464–4479.
