OBJECTIVE: To examine the factors predisposing to initial damage in patients in the LUMINA (lupus in minorities: nature versus nurture) cohort, a multiethnic cohort of patients with systemic lupus erythematosus (SLE) in the US. METHODS: One hundred fifty-eight LUMINA patients with no damage at baseline (time 0) according to the Systemic Lupus International Collaborating Clinics Damage Index (SDI) and with disease duration > 6 months were followed up for a median of 24 months (range 5-112 months). Damage was assessed from time 0 to the last visit. Predictors of time to initial damage were examined by univariable and multivariable Cox proportional hazard regression models. Results were reported as hazard ratios (HRs); HR values > or = 1 indicated a shorter time to initial damage, and values < 1 indicated a longer time. RESULTS: Initial damage occurred in 54 patients (34%), of whom 21 were Hispanics from Texas (39%), 2 were Hispanics from Puerto Rico (4%), 21 were African Americans (39%), and 10 were Caucasians (19%). The most frequently observed initially involved SDI domains (and items) were as follows: renal (primarily proteinuria) in Hispanics from Texas and African Americans, integument (primarily scarring alopecia) in Hispanics from Puerto Rico, and ocular (primarily cataracts) in Caucasians. By multivariable analyses, independent predictors of a shorter time to initial damage were Hispanic ethnicity from Texas (HR 2.11, 95% confidence interval [95% CI] 1.15-3.88), greater disease activity according to the Systemic Lupus Activity Measure (HR 1.09, 95% CI 1.04-1.15), the occurrence of thrombotic events in visceral and/or peripheral veins or arteries (HR 7.66, 95% CI 2.13-27.51), and prednisone at a dosage of < 10 mg/day (HR 2.53, 95% CI 1.15-5.55). Prednisone at a dosage of 10-30 mg/day was found to be protective against the occurrence of initial damage (HR 0.46, 95% CI 0.22-0.96). CONCLUSION: Given that damage is a predictor of further damage, identifying the factors that may herald the occurrence of initial damage has very practical implications for the management of patients with SLE. These results need to be considered when evaluating therapies for SLE.