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 represent a new treatment drug for patients with SSc, and it is currently being evaluated in a double-blind, placebo-controlled phase 3 trial with a larger sample size.

系统性硬化症（Systemic sclerosis, SSc）是一种可导致皮肤及内脏器官纤维化的自身免疫性疾病。尽管已有多项研究揭示了白细胞介素-17（interleukin-17, IL-17）在SSc中的作用，但关于IL-17通路在SSc发病机制与疾病进展中的具体角色，目前尚未达成共识。我们推测激活的IL-17通路或与SSc的发病机制存在关联，因此这项单中心试验旨在评估日本SSc患者多次皮下注射常规剂量布罗达单抗（brodalumab）——一种全人源抗IL-17受体A（IL-17RA）单克隆抗体——的药代动力学、安全性与有效性。据我们所知，本研究是首个评估布罗达单抗抑制IL-17RA对伴中度至重度皮肤增厚的早期弥漫性皮肤型SSc患者纤维化病变影响的试验。本试验共纳入8例伴中度至重度、进展性皮肤增厚的早期SSc患者，所有患者均符合弥漫性皮肤型SSc的美国风湿病学会/欧洲抗风湿病联盟（American College of Rheumatology/European League Against Rheumatism, ACR/EULAR）分类标准，其中7例为女性。所有患者均接受了布罗达单抗治疗。布罗达单抗可带来超出预期的快速显著改善，改良Rodnan皮肤评分（modified Rodnan Skin Score, mRSS）在第4周即快速下降，并在52周的随访期内持续维持。皮损真皮厚度的降低与mRSS的变化趋势一致。在基线时存在指端溃疡的8例患者中，有4例在第24周和第52周时指端溃疡的平均数量较基线有所减少。肺量测定法评估的呼吸功能指标未出现明显变化。本试验中，与基线相比，布罗达单抗可诱导以调节性T细胞（regulatory T-cell, Treg）为主的Treg/辅助性T细胞17（T helper 17, Th17）平衡，减少免疫球蛋白G+（IgG+）类别转换记忆B细胞及浆母细胞的数量，并增加过渡性B细胞的数量。综上，所有患者的mRSS降幅均超过了最小临床重要差异，同时皮损真皮厚度也有所降低。布罗达单抗在减轻SSc纤维化病变方面展现出的快速、持续且显著的高疗效，可能与其对成纤维细胞的直接作用，以及通过改变B细胞和T细胞亚群产生的间接效应有关。此外，布罗达单抗在改善临床症状的同时未出现严重的治疗突发不良事件。上述结果提示，布罗达单抗或可成为SSc患者的新型治疗药物，目前该项试验正开展更大样本量的双盲安慰剂对照Ⅲ期临床试验以进一步验证其疗效。