Diverse pathogenic pathways complicate efforts to improve treatment options for lupus

Lupus has a simple definition that belies the complexity of the disease and the challenge of finding effective treatments for it, according to Virginia Pascual, MD, the featured speaker in the ACR Convergence session Precision Medicine in Lupus 2021.

“Lupus is a very complex disease clinically. It is very complex immunologically as well, even though we could define it with just one sentence: Lupus is a breakdown of tolerance to nucleic acids. This doesn’t happen in most other immune-mediated diseases,” said Dr. Pascual, the Ronay Menschel Professor of Pediatrics and Director of the Drukier Institute for Children’s Health at Weill Cornell Medicine.

Dr. Pascual discussed the heterogeneity and immunologic mechanisms of systemic lupus erythematosus, as well as disease presentation and treatment response, during the one-hour session, which was originally presented Saturday, Nov. 6, and can be viewed by registered meeting participants through March 11, 2022.

Lupus is particularly challenging from a clinical perspective because it can affect almost any organ, complicating its diagnosis and the measurement of disease activity, yet there are no predictors of end-organ involvement, Dr. Pascual noted. What’s more, only three drugs have been approved by the U.S. Food and Drug Administration to treat lupus in the past 65 years — belimumab in 2011, and anifrolumab-fnia and voclosporin in 2021. Multiple drugs targeting different pathogenic pathways have failed in phase 3 clinical trials after showing promise in phase 2 trials.

“Signaling molecules downstream of the interferon-signaling pathway hopefully are going to show success in phase 3 trials, but until we see it, we will be anxious,” Dr. Pascual said.

Genetic studies have shown that the pathogenic pathway of origin has a significant influence on the type of lupus a patient develops. In Dr. Pascual’s research using immune-monitoring technology, patients are followed longitudinally to correlate genomic and transcriptional immune signals with the patient’s laboratory traits and clinical disease.

Last year, Dr. Pascual and her colleagues published the results of a study of pediatric patients. Using peripheral blood mononuclear cells at the single-cell gene expression level, the researchers detected different cell types that were expanded or contracted in lupus patients and then classified the patients into subsets based on B cells. One subset carried an increased expression of interferon-stimulated genes, as well as genes characteristic of the monogenic deficiencies that contribute to lupus, she said. The data prompted the researchers to also look at monocytes, T cells, NK cells, and embryonic cells on a single-cell level to group patients.

“This is going to allow us to understand so much better what is happening to our patients and why they might or might not respond to specific therapy,” Dr. Pascual said.

Researchers also have identified a form of endogenous nucleic acid that contributes to lupus and complements the “tremendous orchestration” of nucleic acid buildup and interferon signaling in the disease, she said.