Introduction <p>Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by dysregulated innate and adaptive immune responses. However, data on immunologic disturbances in SLE flares remains limited. Thus, we aimed to evaluate serum levels of selected cytokines involved in its pathogenesis such as APRIL (a proliferation-inducing ligand), BAFF (B cell activating factor), and interleukin(IL)-10 levels in SLE patients to identify potential biomarkers of disease activity.</p> Patients and methods <p>We investigated 52 patients with SLE: 15 (28.8%) with disease exacerbation (SLE disease activity index [SLEDAI] ≥ 5 points) and 37 (71.2%) in remission (SLEDAI &lt; 5 points), and 12 controls matched by sex and age. All patients met the 2019 EULAR/ACR SLE criteria. Serum levels of APRIL, BAFF, and IL-10 were determined in all participants with the Luminex Discovery Assay Human Premixed Multi-Analyte Kit.</p> Results <p>We observed no significant differences in the serum levels of BAFF, APRIL, and IL-10 between active and inactive SLE patients or between active/inactive SLE patients and healthy controls, but also considering all SLE cases and the control group. There were no differences in the cytokine levels between patients with renal flare and those without renal flare in the active SLE group, but also in the inactive SLE group regarding the presence of lupus nephritis. Correlation analysis revealed a positive association between APRIL and BAFF (<i>r</i>_s = 0.66, <i>p</i> &lt; 0.001), BAFF and IL-10 (<i>r</i>_s = 0.45, <i>p</i> &lt; 0.001), and between APRIL and IL-10 (<i>r</i>_s = 0.36, p = 0.004). Furthermore, regarding clinics, BAFF levels showed a moderate positive correlation with disease duration (<i>r</i>_s = 0.30, <i>p</i> = 0.034), whereas IL-10 levels correlated positively with the SLEDAI score (<i>r</i>_s = 0.34, <i>p</i> = 0.013). We found that anti-dsDNA antibody levels were significantly associated with all analyzed cytokines, including APRIL (<i>r</i>_s = 0.35, <i>p</i> = 0.007), BAFF (<i>r</i>_s = 0.37, <i>p</i> = 0.004), and IL-10 (<i>r</i>_s = 0.41, <i>p</i> = 0.002). In the follow-up analysis, during a median observation period of 5.5&#xa0;years, 10 out of 37 enrolled inactive SLE patients developed a disease flare, but no cytokine differences in baseline levels were found between those with or without a flare in the follow-up period.</p> Conclusions <p>In our study, higher BAFF levels were associated with longer disease duration, while elevated IL-10 levels correlated with the SLEDAI score. Such correlations were not observed considering APRIL. However, all cytokines were also linked to higher anti-dsDNA antibody titers. Nevertheless, no significant differences in serum levels of APRIL, BAFF, and IL-10 were observed between active and inactive SLE patients, but also controls, limiting their potential as biomarkers of disease activity, but also their ability to predict disease flares.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>Serum APRIL, BAFF, and IL-10 levels were similar between active and inactive SLE patients or compared with healthy controls.</i></p> <p>• <i>BAFF correlated positively with disease duration, and IL-10 with the SLEDAI score.</i></p> <p>• <i>None of the cytokines predicted future disease flares during a median follow-up period of 5.5&#xa0;years.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>