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The current systemic treatments mainly consist of conventional systemic agents, biologics targeting tumor necrosis factor (TNF)\u2010\u03b1, interleukin (IL)\u201012\/23p40, IL\u201017, or IL\u201023p19, and targeted oral agents. This review summarizes current evidence on efficacy, long\u2010term disease control, safety, head\u2010to\u2010head comparisons, and practical selection of systemic treatments for adults with moderate\u2010to\u2010severe plaque psoriasis. Older conventional systemic agents, such as cyclosporin, acitretin, or methotrexate, remain useful in selected settings, especially when treatment options are limited by cost or availability, when short\u2010term disease control is needed, or when the patient prefers these treatments. However, these conventional agents require careful monitoring and generally achieve lower rates of complete skin clearance compared to high\u2010efficacy biologics. Biologics targeting TNF\u2010\u03b1 or anti\u2010IL\u201012\/23p40 ustekinumab have established the biologic treatment era, and remain clinically relevant, especially for patients having psoriatic arthritis or prioritizing long\u2010term safety. Biologics targeting IL\u201017 can provide rapid and complete or almost complete skin clearance; however, require attention to mucocutaneous candidiasis and inflammatory bowel diseases. Biologics targeting IL\u201023p19 offer durable treatment responses and longer dosing intervals. Targeted oral therapies increase options for patients who prefer non\u2010injectable treatment; established or emerging agents include apremilast, deucravacitinib, icotrokinra, zasocitinib, envudeucitinib, and orismilast. Emerging IL\u201017\u2010directed agents, including sonelokimab and izokibep, may further refine pathway targeting. Selection of treatment should be decided dependently on the completeness of skin clearance achieved, speed and duration of responses, effectiveness on high\u2010impact sites, safety, route of administration, monitoring requirements, patients' comorbidities, and the treatment goals aimed.<\/jats:p>","DOI":"10.1111\/1346-8138.70457","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:34:40Z","timestamp":1786595680000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Systemic Treatment of Psoriasis: Current Evidence on Efficacy and Safety"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4183-9596","authenticated-orcid":false,"given":"Teppei","family":"Hagino","sequence":"first","affiliation":[{"name":"Department of Dermatology Nippon Medical School Chiba Hokusoh Hospital  Inzai 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