In an interview following the recent Congress of Clinical Rheumatology (CCR) – East 2026, Kenneth Kalunian, MD, discussed how cytokine networks and immune dysregulation may help explain organ system involvement in systemic lupus erythematosus (SLE). He highlighted IFN signaling, plasmacytoid dendritic cell targeting, TLR inhibition, and musculoskeletal disease as important areas of current and future research.

Following the presentations at CCR East 2026, featured expert Kenneth Kalunian, MD, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Kalunian on these findings are presented here.

There is obviously overlap in organ system involvement in patients with SLE, but there is usually a predominance of one organ system over the other. One manifestation supersedes the other(s) in terms of how you approach the patient. The way I look at lupus is from the perspective of what the predominant dysregulated organ systems are displaying. I think that there probably is a predominant phenotype of dysregulation for the different manifestations of SLE, but we just do not know that yet with certainty.

We know that B-cell dysregulation is predominant in renal disease. The IFN pathway is important for skin and probably joints, and it does have a role in the renal manifestations of SLE, but likely not in a predominant way. If you have a lot of IFN around, that is going to stimulate disease in the skin and probably the joints. It will also turn on the adaptive immune system, which is primarily responsible for the dysregulation of the kidney. What is lacking is our ability to really know what the driving factors are for musculoskeletal disease in SLE. We also have no idea what drives hemolytic anemia, thrombocytopenia, or central nervous system disease in SLE. We have anecdotal clues based on what we have used to treat these disease manifestations, but we do not fully understand what the driver is.

Trying to understand what is really driving the patient’s symptomatology and abnormalities is how I approach lupus treatment. The IFN pathway is mainly associated with the skin manifestations of SLE, and we know that blocking IFN (eg, like we did with anifrolumab in the pivotal studies of this drug for SLE) results in a marked improvement in SLE generally, including skin disease. As shown in a study by Vasileios Kyttaris, MD, PhD, and colleagues presented at CCR East 2026, anifrolumab also promotes a significant reduction in oral corticosteroid use in patients with SLE. This really speaks highly of the drug’s effect.

While developing SLE treatments, we have also looked more upstream in the IFN signaling pathway to see if we could decrease the production of IFN at the plasmacytoid dendritic cell level. That is where litifilimab comes in. Basically, litifilimab internalizes a surface marker on plasmacytoid dendritic cells, which, in turn, decreases the release of IFNs into the systemic pool. A signal from the plasmacytoid dendritic cells to the downstream effects at the skin level, for example, is blocked and you do not have the inflammatory response that drives the disease. This blocks the signal from dysregulation of the innate immune system to hyperactivity of the adaptive immune system. The feedback loop is stopped—not 100%, but we are getting there in terms of the efficacies of these drugs.

Notably, an analysis of the phase 3 TOPAZ-1 and TOPAZ-2 litifilimab studies in SLE by Jonathan Kay, MD, et al was also presented at CCR East 2026. The investigators highlighted that these studies enrolled multinational and geographically diverse populations, with notable North American representation, enabling the comprehensive and robust evaluation of litifilimab.

In searching for SLE treatments, we have also looked at TLRs, which are even more upstream than the plasmacytoid dendritic cells. By blocking certain TLRs, we get the same effect observed with litifilimab. That is what all the excitement is about right now. There are other treatments that target promoters of dysregulation of the innate immune system that are coming down the pike for SLE, but they are all in early-stage clinical trials. It will be very exciting to see what is going to happen next.

There is a huge missing piece here, however, which is joint manifestations in SLE. I think that we really have no idea how much this manifestation is due to cytokine pathway dysregulation, B cells or T cells, or B cells interacting together. We do not have it all dialed in yet. I think that we have a lot of good clues as to how we can affect skin and kidneys, but we are not getting 100% cure rates. I believe that the next frontier is the joints, and we have to figure that out.