Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Expert Rev Clin Immunol. 2023 Jul-Dec;19(10):1187-1194. doi: 10.1080/1744666X.2023.2234641. Epub 2023 Aug 8.
Despite ongoing efforts to develop effective therapeutics, no disease-modifying drugs have been officially licensed for the indication of Sjögren's disease (SjD). This is partly due to heterogeneity in disease manifestations, which complicates drug target selection, trial design and interpretation of clinical efficacy in SjD.
Here, we summarize developments and comment on challenges in 1) identifying the right target for treatment, 2) selection of the primary study endpoint for trials and definition of clinically relevant response to treatment, 3) inclusion criteria and patient stratification, 4) distinguishing between disease activity and damage and 5) establishing the effect of treatment considering measurement error, natural variation, and placebo or nocebo responses.
Targets that are involved in both the immune cell response and dysregulation of glandular epithelial cells (e.g. B-lymphocytes, type-I interferon) are of particular interest to treat both glandular and extra-glandular manifestations of SjD. The recent development of composite study endpoints (CRESS and STAR) may be a crucial step forward in the search for clinically effective systemic treatment of patients with SjD. Important additional areas for future research are symptom-based and/or molecular pathway-based patient stratification, prevention of irreversible damage, and establishing the effect of treatment.
尽管一直在努力开发有效的治疗方法，但尚无获批用于干燥综合征（SjD）适应证的疾病修正药物。这部分是由于疾病表现的异质性，这使得药物靶点选择、临床试验设计和临床疗效的解释变得复杂。
本文总结了在以下方面的进展和挑战：1）确定治疗的正确靶点；2）选择临床试验的主要研究终点和对治疗的临床相关反应的定义；3）纳入标准和患者分层；4）区分疾病活动度和组织损伤；5）考虑测量误差、自然变异、安慰剂或无应答效应来确定治疗效果。
涉及免疫细胞反应和腺体上皮细胞失调的靶点（例如 B 淋巴细胞、I 型干扰素）特别有兴趣用于治疗 SjD 的腺体和腺体外表现。最近开发的综合研究终点（CRESS 和 STAR）可能是寻找 SjD 患者临床有效全身治疗的重要一步。未来研究的重要领域还包括基于症状和/或分子途径的患者分层、预防不可逆转的损伤以及确定治疗效果。
