Evidence regarding whether patients with systemic lupus erythematosus (SLE) are at higher risk of disease flare or worsening after SARS‑CoV‑2 infection remains limited. This study aimed to evaluate the clinical symptoms and complication risks in SLE patients infected with the SARS‑CoV‑2 Omicron variant and to identify factors associated with post‑infection lupus flare.

A retrospective case‑control study was conducted, including 157 SLE patients (SLE group) and 148 age‑ and sex‑matched healthy controls (control group) diagnosed with Omicron infection. Data on demographic characteristics, comorbidities, use of immunosuppressants, post‑infection symptoms, and complications were collected via electronic medical records and structured questionnaires. Statistical analyses were performed using independent‑samples t‑tests, chi‑square tests, and multivariate logistic regression.

Although the SLE group had a lower vaccination rate than the control group (45.9% vs 95.3%, P < 0.01) and a higher burden of comorbidities, no significant differences were observed between the two groups in the incidence of pneumonia (3.8% vs 4.7%, P = 0.695) or the proportion of non‑mild COVID‑19 cases (6.4% vs 7.4%, P = 0.714). The proportion of patients reporting typical systemic inflammatory symptoms (e.g., fever, myalgia) after infection was significantly lower in the SLE group compared with the control group (61.8% vs 90.5%, P < 0.05). Among SLE patients, the presence of interstitial lung disease was an independent risk factor for progression to non‑mild COVID‑19 (P=0.024). Multivariate analysis revealed that pre‑infection SLE stability (OR=0.063, 95% CI 0.015-0.270) and maintaining the original immunosuppressive regimen without dose reduction after infection (OR=0.159, 95% CI 0.032-0.784) were significant protective factors against lupus flare.

SLE patients infected with the Omicron variant did not exhibit a higher risk of severe COVID‑19 than the general population and even presented with milder systemic inflammatory symptoms. The overall risk of lupus flare after infection was low, with the key protective factors being stable disease before infection and continued immunosuppressive therapy during infection. These findings suggest that glucocorticoids/immunosuppressants should not be arbitrarily reduced or discontinued during Omicron infection, and that SLE patients may experience a clinical course of COVID‑19 similar to that of the general population.