Early SLE may follow a fast comorbidity/multimorbidity trajectory associated with flare burden and glucocorticoid...

Patients with systemic lupus erythematosus (SLE) carry a substantial comorbidity load associated with worse prognosis, yet most evidence pertains to long-standing disease. How comorbidities-particularly multimorbidity as a marker of overall health burden-evolve at early stages, and whether conditions co-aggregate into clinically meaningful clusters, remains unclear.

An inception cohort (≤2 years from diagnosis) of 311 patients with SLE with 5-year monitoring of 140 comorbidities, disease activity, treatments, organ damage and adverse events/hospitalisations. Growth mixture modelling identified trajectories of incident comorbidities, while tetrachoric exploratory factor analysis followed by clustering defined multimorbidity profiles; these trajectories and profiles were then related to longitudinal outcomes. To inform temporal ordering, trajectory modelling was refitted for months 24-60, and predictors from <24 months were evaluated using penalised multivariable regression.

Early SLE separated into slow (55%) and fast (45%) incident-comorbidity trajectories. Among fast accruers, three phenotypes emerged: low-to-moderate (general/non-patterned) (51%), metabolic-psychiatric (31%) and cardiopulmonary-musculoskeletal (18%), with a gradual increase in multimorbidity (≥2 conditions) (32.7%, 65.7% and 100%, respectively). Compared with slow-accruing, fast-accruing patients-especially the metabolic-psychiatric and cardiopulmonary-musculoskeletal-attained less lupus low disease activity state/Definition of Remission In SLE and developed more damage (incidence rate ratio (IRR) 2.28-3.27) and safety-related events (IRR 1.89-3.36). Severe flares (≥20% of time; OR 2.10, 95% CI 1.09 to 4.04) and glucocorticoid exposure (OR 1.06 per 10 mg/day, 95% CI 1.01 to 1.11) during the first 24 months independently predicted subsequent fast-comorbidity trajectory. Flares were more prominent in the fast/low-to-moderate and metabolic-psychiatric phenotypes, whereas glucocorticoid use was more prominent in the cardiopulmonary-musculoskeletal phenotype.

Nearly half of patients with newly diagnosed SLE show accelerated comorbidity and multimorbidity burden, underscoring the need for clinical vigilance. Fast-accrual phenotypes are linked to flares and glucocorticoid exposure, two potentially modifiable features of early disease.