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Introduction Respiratory manifestations are common among patients with Systemic Lupus Erythematosus (SLE) and can present as chest pain, dyspnea, and cough and are often accompanied by fever. These symptoms can resemble those of COVID-19, which may cause increased anxiety in SLE patients. Therefore, the aim of this study is to investigate the impact of SLE-related respiratory manifestations on anxiety, depression, and quality of life among SLE patients during the COVID-19 pandemic. Patients and methods The study involved SLE patients and was conducted in the year 2020, after the start of the pandemic in Morocco, using a cross-sectional design. Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale (HADS), while the quality of life was assessed using the Short Form-12 Health Survey (SF12). Statistical analysis was performed using R software (R Foundation, Vienna, Austria). Results A total of 102 SLE patients, with an average age of 41.6 ± 13.7 years, participated in the study, of whom 92.2% were female. Respiratory manifestations were reported by 20.6% of the patients, and there were no significant differences observed in the general characteristics of the study population between the two groups with and without SLE-related respiratory manifestations. The study found that the prevalence of anxiety and depression was significantly higher in patients with SLE-related respiratory manifestations (50% Vs. 76,2% and 50% Vs. 85,7% successively). These patients also reported significantly more impairment in their physical quality of life (31.8 ± 8.9 Vs. 38.5 ± 10.9). This was observed across three domains of the SF12 survey, including physical functioning (34.4 ± 11.4 Vs. 39.9 ± 11.7), bodily pain (26.9 ± 11.2 Vs. 36.1 ± 14.3), and general health (28.6 ± 10.7 Vs. 35.2 ± 12.3). Although the association between mental quality of life and respiratory manifestations did not reach statistical significance (33.5 ± 12.5 Vs. 39.1 ± 11.5), there was a trend toward poorer mental quality of life in patients with SLE-related respiratory manifestations. Moreover, two domains of mental quality of life were significantly more affected in these patients, namely "social functioning" (30.6 ± 11.3 Vs. 38.7 ± 12.4) and "role-emotional" (26.8 ± 11.6 Vs. 33.8 ± 10.8). Conclusion During the COVID-19 pandemic, the presence of SLE-related respiratory manifestations appeared to be associated with a more negative impact on the psychological health and quality of life of SLE patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, El Harch et al.)