New Data Suggest Biomarker for SLE Therapy Response

A new study has identified biomarkers that may help predict which patients with systemic lupus erythematosus (SLE) are most likely to respond to B-cell–directed therapies.

The report, published in The Lancet Rheumatology, also found that certain distinct molecular networks were associated with renal and mucocutaneous involvement. The authors cautioned that these results would need to be confirmed in larger studies.

A major challenge in treating patients with SLE is that the disease can have widely divergent clinical presentations, with differing symptoms and organ involvement from patient to patient. The study authors said the production of autoantibodies such as double-stranded DNA (dsDNA) are a “hallmark” of SLE, making B-cell–targeted therapies like Rituxan (rituximab) a logical choice for treating patients.

“However, considerable variation in response to rituximab has been noted, and randomized clinical trials have not shown an overall benefit,” they said.

Benlysta (belimumab) is a B-cell–activating factor (BAFF) neutralizing monoclonal antibody. In a previous placebo-controlled trial (BEAT-LUPUS), the investigators showed that prescribing belimumab following rituximab significantly reduced serum immunoglobulin G anti-dsDNA antibody concentrations, as well as the risk of severe flares, in a cohort of patients with SLE refractory to conventional therapy.

The authors therefore decided to use samples from BEAT-LUPUS to see whether they could identify biomarkers that indicated which patients were most likely to respond to belimumab following rituximab.

They recruited 52 patients from BEAT-LUPUS. Fifty-two week data were available for 44 patients, and those patients were included in the final analysis. Of those, 21 patients were in the belimumab group and 23 were in the placebo group. The groups had median ages of 39.5 and 42.1 years, respectively. Both groups were composed of a majority of female patients and White patients.

The authors found that serum immunoglobulin A2 (IgA2) anti-dsDNA antibody concentrations were the only predictive biomarker of response to belimumab after rituximab.

“We found a predictive association between baseline serum IgA2 anti–dsDNA antibody concentrations and clinical response to belimumab after rituximab, with a between-group difference in major clinical response of 48% (95% CI, 10%-70%) in patients with elevated baseline serum IgA2 anti-dsDNA antibody concentrations,” the authors wrote.

They also found that serum IgA2 anti-dsDNA antibody concentrations were associated with active renal disease. Serum IgA1 anti-dsDNA antibody and interferon-α concentrations were associated with mucocutaneous disease, they said.

“Patients with a high baseline serum interleukin-6 concentration were less likely to have a major clinical response, irrespective of therapy,” they wrote.

Their study had several limitations, they noted. For instance, they said flow cytometry could not be completed on all of the patients in the BEAT-LUPUS study due to limited capacity at medical centers participating in the study, and they said it might be difficult to translate these findings into clinical practice.

“If IgA2 anti-dsDNA antibodies are to be measured in routine clinical practice, the ELISA assay we used will need to be commercially validated in a similar manner to IgG anti-dsDNA antibody assays and the results confirmed in a larger clinical trial,” they wrote.

Still, the authors said their findings offer an important glimpse that may help clinicians better understand which patients are most likely to benefit from belimumab after rituximab combination therapy.

Reference
Shipa M, Santos LR, Nguyen DX, et al. Identification of biomarkers to stratify response to B-cell-targeted therapies in systemic lupus erythematosus: an exploratory analysis of a randomised controlled trial. Lancet Rheumatol. Published online November 28, 2022. doi:10.1016/s2665-9913(22)00332-0