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Despite increasing interest in biological therapies for pSS, achieving FDA-approval has been challenging due to numerous complications in the trials. The current literature lacks insight into a molecular-target-based approach to the development of biological therapies. This review focuses on novel research in newly defined drug targets and the latest clinical trials for pSS treatment. A literature search was conducted on ClinicalTrials.gov using the search term \u201cPrimary Sj\u00f6gren\u2019s syndrome\u201d. Articles published in English between 2000 and 2021 were included. Our findings revealed potential targets for pSS treatment in clinical trials and the most recent advances in understanding the molecular mechanisms underlying the pathogenesis of pSS. A prominent gap in current trials is in overlooking the treatment of extraglandular symptoms such as fatigue, depression, and anxiety, which are present in most patients with pSS. Based on dryness and these symptom-directed therapies, emerging biological agents targeting inflammatory cytokines, signal pathways, and immune reaction have been studied and their efficacy and safety have been proven. Novel therapies may complement existing non-pharmacological methods of alleviating symptoms of pSS. Better grading systems that add extraglandular symptoms to gauge disease activity and severity should be created. The future of pSS therapies may lie in gene, stem-cell, and tissue-engineering therapies.<\/jats:p>","DOI":"10.3390\/ijms232214135","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:24:53Z","timestamp":1668565493000},"page":"14135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Future of Targeted Treatment of Primary Sj\u00f6gren\u2019s Syndrome: A Focus on Extra-Glandular Pathology"],"prefix":"10.3390","volume":"23","author":[{"given":"Weizhen","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences, Beijng 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulan","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruihua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences, Beijng 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2266-7469","authenticated-orcid":false,"given":"Chrystie Wan Ning","family":"Quek","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haozhe","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan Yong Kiat","family":"Tay","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9065-2744","authenticated-orcid":false,"given":"Xiang","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, The University of Hong Kong, Hong Kong SAR, China"},{"name":"State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9453-3259","authenticated-orcid":false,"given":"Yun","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1146\/annurev-med-043015-123313","article-title":"Mechanisms and New Strategies for Primary Sj\u00f6gren\u2019s Syndrome","volume":"68","author":"Mavragani","year":"2017","journal-title":"Annu. 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