Written By: Leah Bettner, Shruti Chandramouli, Amanda Lusa, Christopher Overton, and Enid Sun, University of North Carolina
Topic Overview
SLE pathophysiology is characterized by the development of pathogenic autoantibodies by plasma cells. Currently there are SLE therapies that target early stages of B-cell development to prevent autoantibody production, including anti-CD20 and anti-BAFF monoclonal antibodies. However, long-lived plasma cells do not respond to these available treatments. As such, specifically targeting the plasma cell source of autoantibody production is therapeutically attractive. Plasma cells express the glycoprotein CD38. Daratumumab is a CD38-directed monoclonal antibody that is currently used to deplete malignant plasma cells in multiple myeloma. Extension of daratumumab as a viable treatment option for refractory SLE was upheld in this proof of concept report. Two patients with life-threatening SLE refractory to traditional treatment options were treated with a 4-week course of daratumumab followed by maintenance therapy with belimumab after four months. Treatment resulted in highly favorable response rates in major organ involvement including lupus nephritis, pericarditis, and autoimmune hemolytic anemia. Organ-specific response rates were accompanied by improvement in serum serological markers of disease activity and SLEDAI-2K scores over the course of 11-12 months of follow-up. Post-treatment flow cytometry and transcriptome analysis demonstrated that the benefits of anti-CD38 therapy extended beyond plasma cell targets. Treatment resulted in reduction of CD38 expressing natural killer cells, plasmacytoid dendritic cells, CD19+ B-cells, and decreased T-cell activation and interferon signaling. Overall this report suggests that daratumumab is a potential therapy for refractory SLE.
Implications for Patients, Providers, & Researchers
Current implications: This study raises consideration for the following: 1) Plasma cells amongst other CD38+ cells contribute to SLE pathogenesis; 2) Targeting the CD38 glycoprotein promotes depletion of long-lived plasma cells and when used concomitantly with belimumab results in favorable clinical outcomes for patients with refractory SLE. This study highlights how the SLE treatment armamentarium would benefit from further research into plasma-cell depleting therapies.
Future implications: This study sets the stage for further investigation into a novel treatment modality for SLE. The exact mechanism of action of daratumumab in SLE pathophysiology remains speculative and warrants further evaluation to confirm its unique targeting mechanism and downstream immunologic and clinical effects. The current data is cautiously optimistic. However, the positive outcomes will likely prompt further investigation into larger safety studies and ultimately clinical trials. If larger randomized trials are ultimately pursued, concurrent treatment with belimumab might be considered as part of a multimodal B cell-targeting strategy. Clinicians treating patients with highly refractory SLE might consider daratumumab as an off-label therapeutic strategy and should stay tuned for potential future clinical trial enrollment options for anti-CD38 therapy.
Will Daratumumab Win its First Round Match-up?
Daratumumab is difficult to compare to its VEXAS opponent. The VEXAS study identifies a new systemic disease which will certainly prompt further studies into pathogenesis and ultimately treatment considerations. The Daratumumab study identifies a new treatment for an already well-defined systemic disease. A clear advantage Daratumumab has over VEXAS is the suspected far-reaching fan base of SLE patients who will show up to support the Daratumumab team. The VEXAS fan base is still to be determined and without the support of a crowd, our opponent might falter against Daratumumab.
Could Daratumumab Win it All?
While it is easy to underestimate this small but mighty Daratumumab team, the exciting future therapeutic implications for refractory SLE could help it win the entire tournament. Although the study reviewed only two cases, the fact that it was published in the high-impact New England Journal of Medicine shows that there is great potential for this team to go all the way. However, if Daratumumab gets past the first round against VEXAS, it will have to face formidable opponents RP Subtypes or IgG4-RD Classification Criteria, both important studies helping to classify multi-organ system, rare diseases with many overlapping manifestations. If successful, it will then have to face the powerhouse teams of SLE and ANCA, all of which have significant clinical implications. However, the potential to use daratumumab for the sickest of our SLE patients could help it win it all!
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