Abstract: Introduction: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by multi-organ involvement and variable clinical manifestations. Recurrent clinical patterns suggest distinct phenotypes, where cluster analysis of autoantibodies could identify prognostic subtypes. Objectives: To define and describe serological clusters and their clinical-epidemiological characteristics, as well as their association with comorbidities, disease activity measures, severity, and damage. Materials and methods: Descriptive, observational, and multicenter study including SLE patients from the Spanish Registry RELESSER. Gower distance was used for cluster analysis. Results: A total of 1,740 patients from the cross-sectional phase and 718 from the prospective phase with a four-year follow-up were included. Four serological clusters were identified. Cluster 1 (negative for extractable nuclear antigen [ENA]) was characterized by a lower frequency of vasculitis, leukopenia, and lymphopenia. Cluster 2 (positive antiphospholipid antibodies) more frequently presented haemolytic anaemia, thrombocytopenia, vasculitis and visual alterations and required greater use of immunoglobulins and oral anticoagulants. Cluster 3 (positive anti-SSA/Ro and anti-SSB/La) had a lower incidence of lupus nephritis. Cluster 4 (positive anti-Sm and anti-ribonucleoproteins) was characterized by higher rates of lupus nephritis, leukopenia, lymphopenia, hypocomplementemia, myositis and cutaneous manifestations and greater use of glucocorticoids and immunosuppressants. Patients in cluster 2 had higher baseline damage scores measured by the SLICC/ACR DI (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), while patients in cluster 4 had higher severity scores measured by the Katz Index. These differences among clusters persisted over the four-year of follow-up. Conclusion: In our SLE patient population, the serological profile is key not only for clinical stratification but also for prognostic value.
