Short-Term Metabolic and Inflammatory Effects of Upadacitinib in Biologic-Refractory Spondyloarthritis: Real-World Evidence on Lipid Paradox and Safety

<b>Background:</b> Upadacitinib (UPA), a selective Janus kinase 1 (JAK1) inhibitor, is an established therapeutic option for spondyloarthritis (SpA). Although its clinical efficacy has been demonstrated in randomized trials, real-world evidence regarding its early metabolic effects-particularly in the context of the inflammatory "lipid paradox"-remains limited. This study aimed to evaluate the short-term impact of UPA on inflammatory, hematologic, and metabolic parameters in a biologic-refractory SpA cohort. <b>Methods:</b> This retrospective cohort study included 61 patients (51 with ankylosing spondylitis and 10 with psoriatic arthritis) who had an inadequate response to tumor necrosis factor inhibitors (TNFi-IR). The study evaluated the short-term effects of UPA treatment on disease activity, inflammatory markers, and lipid-related atherogenic risk, as assessed using the LDL/HDL ratio, over a three-month period. Demographic characteristics, disease activity (BASDAI), inflammatory markers (CRP, ESR), safety parameters (creatine kinase [CK], ALT, AST), and lipid profiles were assessed at baseline, Month 1, and Month 3. <b>Results:</b> The mean age was 42.6 ± 10.8 years. By Month 3, UPA treatment resulted in significant reductions in BASDAI (5.8 ± 1.4 to 3.6 ± 1.2, <i>p</i> < 0.001), CRP (11.4 ± 10.2 to 6.9 ± 5.8 mg/L), and ESR (<i>p</i> < 0.01). Hemoglobin and albumin levels increased significantly (<i>p</i> < 0.05), while liver enzymes remained stable. CK levels demonstrated a modest but statistically significant increase without exceeding three times the upper limit of normal and without clinical evidence of myopathy. Total cholesterol, LDL-C, and HDL-C increased significantly (<i>p</i> ≤ 0.003); however, triglycerides and the LDL/HDL ratio remained unchanged (<i>p</i> > 0.05). No significant differences in inflammatory or metabolic responses were observed between ankylosing spondylitis and psoriatic arthritis subgroups (<i>p</i> > 0.05). <b>Conclusions:</b> In biologic-refractory SpA patients, upadacitinib provides rapid anti-inflammatory and clinical benefits. Although quantitative increases in lipid subfractions were observed, the stability of the LDL/HDL ratio suggests a balanced metabolic recalibration consistent with inflammation control rather than an immediate pro-atherogenic shift. These findings highlight the importance of early lipid monitoring and individualized cardiovascular risk assessment while maintaining the therapeutic advantages of JAK1 inhibition in complex SpA populations.