Systemic Treatment Strategies for Patients with Psoriasis and Psoriatic Arthritis in the Setting of ANA Positivity or Lupus Spectrum Disease: A Comprehensive Systematic Review

Background: Psoriasis and psoriatic arthritis (PsA) occasionally coexist with antinu-clear antibody (ANA) positivity, cutaneous lupus erythematosus (CLE), or systemic lupus erythematosus (SLE), creating one of the most challenging therapeutic overlap scenarios in immunodermatology. Divergent immune pathways—IL-23/Th17-driven psoriatic inflammation versus type I interferon–mediated autoimmunity—generate unique vulnerabilities when systemic treatments are used. Objectives: To synthesize treatment outcomes, lupus-related safety signals, and mechanistic insights across systemic therapies in patients with psoriasis or PsA who also exhibit ANA positivity, CLE, or SLE. Methods: A systematic review following PRISMA 2020 guidelines was performed across PubMed/MEDLINE, Embase, Cochrane, Scopus, and ClinicalTrials.gov. Thir-ty-three eligible reports (29 unique clinical studies; 1,429 patients) were included and organized into six prespecified overlap subgroups. Mechanistic and translational studies—including ustekinumab and deucravacitinib SLE trial data and IL-17 inhibi-tor–induced CLE reports—were incorporated for contextual interpretation. Results: IL-23 inhibitors demonstrated the most favorable cross-disease safety, show-ing no signal for CLE worsening, SLE flares, or drug-induced autoimmunity. IL-17 in-hibitors maintained excellent psoriatic efficacy but showed a consistent association with de novo or exacerbated CLE. TNF-α inhibitors carried the highest risk for ANA seroconversion, dsDNA induction, drug-induced lupus, and lupus flares. Ustekinumab exhibited a stable safety profile across lupus-spectrum disease despite mixed efficacy in formal SLE trials. TYK2 inhibition provided dual modulation of IL-23 and type I in-terferon pathways and showed emerging utility in psoriasis/PsA with CLE or SLE. Apremilast, methotrexate, and mycophenolate mofetil remained reliable non-biologic options. Phototherapy required caution in ANA-positive or lupus-susceptible popula-tions. Conclusions: IL-23 inhibition and TYK2 inhibition appear to offer the most balanced combination of efficacy and safety for psoriatic disease complicated by lupus-spectrum autoimmunity. IL-17 inhibitors and TNF-α inhibitors warrant caution or avoidance in CLE- or SLE-prone patients. Personalized treatment should integrate psoriatic versus lupus disease dominance, ANA/ENA profile, CLE subtype, and mechanistic risk. Pro-spective, biomarker-driven studies are needed to guide therapy in this increasingly recognized overlap population. (PROSPERO registration: CRD420251241279).