Understanding lupus processes helps identify ‘important targets’ for intervention
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Ongoing research into the disease processes of lupus has yielded an increased number of therapeutic targets, according to a presenter at the 2024 Association of Women in Rheumatology annual conference.
“We think about lupus based on its many, many clinical manifestations,” Mary K. Crow, MD, physician-in-chief emerita and senior scientist at the Hospital for Special Surgery Research Institute, told attendees. “Heterogeneity comes up as a descriptor, but we have made quite a bit of progress about what underlies this disease.”
In addition to the interferon pathway, Crow mentioned anti-RNA autoantibodies like anti-Ro, anti-La, anti-SM and anti-RNP, along anti-dsDNA autoantibodies and toll-like receptors (TLR), as potential targets for intervention.
The anti-RNA autoantibodies are sustained in patients with lupus over time, according to Crow.
“Their regulatory capacity is important for us to recognize,” she said. “If we do not target these antibodies, they are going to continue to modulate disease.”
Conversely, anti-dsDNA antibodies are not sustained over time.
“They fluctuate over many years,” she said.
A growing body of evidence suggests that targeting toll-like receptors may have a greater role in lupus treatment in the future, according to Crow.
“TLR-7 may be ground zero for driving disease activity in SLE,” she said. “There is lots of it. If you stimulate it, a lot of downstream events that are relative to lupus happen.”
Crow added that, as researchers push to gain further understanding of these processes, one important question emerges.
“How do we take all of this and think about what would be the most rational approach to therapy?” she said.
According to Crow, several of those approaches include hydroxychloroquine; B-cell targeting agents rituximab (Rituxan, Genentech), obinutuzumab (Gazyva, Genentech) and belimumab (Benlysta, GlaxoSmithKline); the interferon targeting agent anifrolumab (Saphnelo, AstraZeneca); and the calcineurin inhibitor voclosporin (Lupkynis, Aurinia).
“Clinicians struggle with when to use one and when to use the other,” Crow said.
Although Crow acknowledged that there are still questions surrounding hydroxychloroquine, there are enough data to support its use in lupus.
“It can impact TLR and autoantigen presentation,” she said. “It probably does have a role in protecting organs from damage. Anyone who can be on it should be on it.”
Regarding B-cell targeting agents, one advantage of belimumab is that there are follow-up data through 5 years, according to Crow.
She added that data for both of these agents indicate that they may be preventing organ damage in patients with lupus.
“As imperfect as it is, the data is very helpful to give us confidence that we are on the right track,” she said.
Similarly, while rituximab has had a “checkered course” in rheumatology clinical trials, obinutuzumab has been modified to make it more effective, according to Crow.
“It is a better B cell depleter,” she said of obinutuzumab. “B-cell depletion has become pretty clearly an important target in lupus therapy.”
Meanwhile, the approval of voclosporin provided hope for patients with lupus nephritis.
“Voclosporin has at least two targets,” Crow said, noting that the calcineurin inhibitor may act on both T cells and podocytes.
However, it is not fully understood whether these two targets work synergistically.
Looking ahead, Crow stated that “a lot has been said” about CAR T-cell therapy in lupus. However, she added that the extent to which immune system depletion is necessary prior to the procedure remains unknown.
“Is this perhaps problematic?” she said. “There may be ways to deliver CAR T cells without the dramatic knocking out of the immune system.”
Toxicities and neurological complications with this procedure also must be watched closely, according to Crow.
“The target is going to be very, very critical,” she said. “We need all this data to help us understand what are the drivers and important products in lupus.”
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Crow MK. SLE: Pathogenic Mechanisms and Therapeutic Opportunities Presented at: Association of Women in Rheumatology annual conference; July 25-27, 2024; Orlando, Florida (hybrid meeting).
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