Year in Preview Examines Outlook for Biomarkers, CAR-T Therapy, Anti-Obesity Drugs, and Other Emerging Therapies in Rheumatic Disease

One of the sessions on the final day of ACR Convergence 2024 examined new developments that are expected to play a pivotal role in patient care and outcomes for individuals living with rheumatic disease.

“My job today is to do a preview, not a review, so that we start to think about the things we learned here at ACR Convergence that may expand going forward,” said Grace Wright, MD, PhD, FACR, private practice Rheumatologist and President, Association of Women in Rheumatology. “One of those is the question, ‘Is there a world in which we can use biomarkers instead of tissue biopsy?’”

The answer is a resounding yes, Dr. Wright said during Clinical Year in Preview on Tuesday, Nov. 19. Unlike the familiar year-in-review sessions that look back at key developments, the Year in Preview focused on key presentations that are most likely to impact patient care. The session will be available on-demand to all registered ACR Convergence 2024 participants through Oct. 31, 2025, by logging into the meeting website.

Abstract 1642 presented a novel urinary biomarker panel with the potential to replace kidney biopsies to assess both the histology of lupus nephritis and the likelihood of active disease. Where proteinuria reflects a broad spectrum of kidney disease, this panel includes a set of 12 proteins linked to intrarenal inflammation. An improvement in the biomarker panel at three months predicted clinical response at one year.

“This is titillating that we may be able to use a biomarker panel to aid in both the diagnosis and longitudinal assessment and to guide treatment decisions in lupus nephritis,” Dr. Wright said.

She noted that the panel might also replace kidney biopsy for patients who cannot access tissue biopsy centers.

Abstract 1646 described the disruption of a novel E3 ligase, E3-X, which increased glucocorticoid-induced leucine zipper (GILZ) abundance and suppressed the pathogenic innate and adaptive immune mechanisms in systemic lupus erythematosus (SLE). Therapies that inhibit E3-X appear to provide the beneficial effects of glucocorticoids while minimizing toxicities and could play important roles in SLE and other diseases.

Two key abstracts addressed cell therapy in rheumatic diseases. The phase I/II CASTLE basket study used a CD19 chimeric antigen receptor T-cell (CAR-T) with a second-generation CAR/4-1BB payload. The agent showed efficacy in SLE, idiopathic inflammatory myopathy, and systemic sclerosis with minimal cytokine release syndrome (CRS) and no reports of immune effector cell-associated neurotoxicity syndrome (ICANS).

A second study, Breakfree-1, used a CD19-directed CAR-T therapy with next generation manufacturing.

“The beauty of this concept is shortening development of the product that goes back into the patient,” Dr. Wright said. “This process shortens the time in terms of clinical responses in patients with SLE.”

Abstract L1 presented a novel CD3/CD19 T-cell engager, A-319, in severe or refractory SLE. The agent showed no evidence of CRS, ICANS, or other safety issues commonly seen in T-cell-mediated B-cell-depletion therapies. Treatment evidenced B-cell depletion, autoantibody reduction, and organ function improvement as early as the second week and appeared to normalize the B-cell repertoire in patients with SLE.

Abstract 2259 explored the effects of anti-obesity medications (AOMs) in patients with rheumatoid arthritis (RA). An analysis of FORWARD registry data indicates that AOMs may be associated with improvement in both cardiovascular disease risk and pain for patients with RA. AOMs were associated with significant weight loss and pain reduction in these patients.

Dr. Wright said combination therapy with AOMs and biologic or traditional disease-modifying antirheumatic drugs (DMARDs) could optimize control of RA and other immune-mediated inflammatory diseases.

Stepping back along the clinical pathway to basic science, Abstract 2531 described a CRISPR deletion screen in fibroblasts that identified novel regulators of inflammation in RA.

“This approach can be used to get a better understanding of what pathways we need to work at interfering within fibroblasts,” said Christopher Ritchlin, MD, MPH, Professor of Allergy/Immunology and Rheumatology, University of Rochester Medical Center. “This is going to have a huge impact on how we think about treating fibroblastic disorder, not only in rheumatoid arthritis, but others as well.”

Abstract 1754 targeted specific T-cell subsets in axial spondyloarthritis. Peripheral blood, synovial tissue, and synovial fluid all carry T-cell receptor beta chain variable (TRBV)-positive cells that recognize human and bacterial peptides. A TRBV9-targeted bispecific T-cell-engaging antibody depletes TRBV9 T-cells without affecting global immunosuppression.

Screening individual patients for their own pathogenic TRBVs and creating a specific antibody could have a significant impact on multiple T-cell-mediated diseases, Dr. Ritchlin noted.

Abstract 1709 focused on sex-related differences in psoriatic arthritis and found 541 differentially expressed proteins (DEPs) in males, 31 DEPs in females, and 200 shared proteins. These sex-specific pathways affect immune cell function, cytokine signaling, and intracellular signaling.

“This is an area I think we are going to see more work in, plumbing the biologic differences that may be underlying these differences in response,” Dr. Ritchlin said.

Dr. Ritchlin also focused on the 12-protein urinary panel described in Abstract 1642. The novel panel showed the strongest correlation for proliferative lupus nephritis.

“If the finding is validated, we can, instead of putting a patient through a renal biopsy, use urinary proteins to predict histology and the response to therapy over time without having to poke the kidney,” he said. “This could be quite revolutionary.”