Interleukin-17 pathway inhibition with brodalumab in early systemic sclerosis: analysis of a single-arm, open-label, phase 1 trial

Systemic sclerosis (SSc) is an autoimmune disease that causes fibrosis of the skin and internal organs. Despite several studies reporting the role of interleukin-17 (IL-17) in SSc, no consensus exists regarding the role of the IL-17 pathway in SSc pathogenesis and progression. We hypothesize a possible relationship between the activated IL-17 pathway and the pathogenesis of SSc; therefore, this single-center trial assessed the pharmacokinetics, safety, and efficacy of multiple subcutaneous injections of the commonly used dosage of brodalumab, a fully human anti–IL-17 receptor A (IL-17RA) monoclonal antibody, in Japanese patients with SSc. To the best of our knowledge, this is the first study assessing the effect of IL-17RA inhibition with brodalumab on human fibrotic lesions in patients with early diffuse cutaneous SSc with moderate-to-severe skin thickening. Eight patients with early SSc involving moderate-to-severe and progressive skin thickening were enrolled. All patients had diffuse cutaneous SSc and met the ACR/EULAR classification criteria for SSc. Seven of the eight patients were women. All patients were treated with brodalumab. Brodalumab demonstrated a greater than expected rapid and significant reduction in the modified Rodnan Skin Score (mRSS), which decreased rapidly at week 4 and was sustained over 52 weeks. A reduction in dermal thickness in the lesional skin was observed consistently with changes in mRSS. In four of the eight patients with finger digital ulcers at baseline, a decrease in the mean number of digital ulcers from baseline was observed at weeks 24 and 52. No changes were observed in the measures of respiratory function assessed by spirometry. In this trial, brodalumab induced a regulatory T-cell (Treg)–dominant Treg/T helper 17 (Th17) balance, decreased the number of immunoglobulin G+ class–switched memory B cells and plasmablasts, and increased the number of transitional B cells compared with those at baseline. In summary, all patients had a decrease in mRSS that exceeded the minimal clinically important difference, together with a reduction in dermal thickness. This rapid, sustained, and significantly high efficacy of brodalumab in reducing fibrotic lesions in SSc could be attributed to its direct effects on fibroblasts and indirect effects by altering B-cell and T-cell subsets. Brodalumab also ameliorated clinical symptoms without any serious treatment emergent adverse events. These results suggest that brodalumab may represe